Fast Disintegrating Cannabinoid Tablets

ABSTRACT

The present invention relates in a first aspect to a fast disintegrating cannabinoid tablet, the tablet comprising a sugar alcohol composition comprising one or more sugar alcohol particles in an amount of at least 20% by weight of the tablet, a cannabinoid composition comprising one or more cannabinoids, and a disintegrant composition comprising one or more disintegrants operable to disintegrate the tablet within a period of 2 minutes or less in contact with oral saliva. In a second aspect, the invention relates to a modular tablet, wherein the tablet comprises a further tablet module that is different in composition.

FIELD OF THE INVENTION

The invention relates to the field of oral delivery vehicles foralleviation or treatment of a condition with one or more cannabinoids.In particular, the invention relates to fast disintegrating tablets fororal administration of one or more cannabinoids.

BACKGROUND OF THE INVENTION

Cannabinoids are a group of chemicals found in Cannabis sativa, Cannabisindica, Cannabis ruderalis, Marijuana plant and related plant species.They are known to activate cannabinoid receptors (CB1 and CB2). Thesechemicals are also produced endogenously in humans and other animals.Cannabinoids are cyclic molecules exhibiting particular properties suchas being lipophilic, have the ability to easily cross the blood-brainbarrier, and having low toxicity.

Cannabis sativa contains more than 400 chemicals and approximately 120cannabinoids, the active constituents of cannabis, includingtetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN),tetrahydrocannabivarin (THCV) and cannabigerol (CBG). Pharmacologically,the principal psychoactive constituent of cannabis istetrahydrocannabinol (THC), which is used for treating a wide range ofmedical conditions, including glaucoma, AIDS wasting, neuropathic pain,treatment of spasticity associated with multiple sclerosis, fibromyalgiaand chemotherapy-induced nausea. THC is also effective in the treatmentof allergies, inflammation, infection, depression, migraine, bipolardisorders, anxiety disorder, drug dependency and drug withdrawalsyndromes.

Cannabinoid delivery methods have been the attention of more and moreinterest in recent years. Lung delivery is most commonly achieved bysmoking cannabis. However, there are health concerns for this mode ofadministration. Cannabis smoke carries even more tars and otherparticulate matter than tobacco. Furthermore, many patients find the actof smoking unappealing, as well as being generally unhealthy.

Attempts have been made to overcome some of the problems associated withsmoking both cannabis and tobacco by providing various smokelessinhalable aerosol formulations for lung delivery. These formulationswere found to be of varying effectiveness in delivering the active agentto the lungs and compliance was an issue even with proper training onthe use of inhalation devices.

In formulating tablets, various challenges are associated with obtaininga homogenous mixture where variations are avoided and a safe andconvenient delivery may be obtained. Also, the general formulation ofthe tablets offering convenience to the user need not be compromisedwhich is often the case if conventional delivery means are applied.

One of the challenges with tablets as a delivery vehicle of cannabinoidsis that cannabinoids tend to be associated with off notes duringadministration due to the specific physiochemical properties of thecompounds. The taste masking challenge is more profound when a higherrelease of cannabinoids are intended in tablets for oral administration.If off-notes are the predominant sensation during administration,convenience may be affected and even more critically, the delivery ofcannabinoids may also be affected. Saliva production may be suppressed,and the delivery vehicle may not be handled correctly.

Furthermore, it is important that a formulation is provided that mayalso help in obtaining a release profile of cannabinoids that offersincreased convenience and effectiveness. In general, less attention isgiven in the prior art on the impact of the tablet formulation for thesensorics properties of oral cannabinoid delivery. Here, importantsensorics properties include friability, hardness, texture, flavorperception, sweetness perception and off-notes associated withcannabinoids. These properties are both relevant from a convenienceperspective in tablets for oral administration, but certainly also inorder to support an appropriate delivery of cannabinoids from tabletsand avoid adverse side effects of cannabinoids.

Hence, there is a need in the prior art for improved tablet formulationsthat solve the above-referenced challenges and problems of the priorart. In particular, there is a need in the prior art for new tabletsthat support appropriate fast delivery of cannabinoids combined withbeneficial sensorics properties.

SUMMARY OF THE INVENTION

Accordingly, in one aspect of the invention there is provided a fastdisintegrating cannabinoid tablet, the tablet comprising a sugar alcoholcomposition comprising one or more sugar alcohol particles in an amountof at least 20% by weight of the tablet, a cannabinoid compositioncomprising one or more cannabinoids, and a disintegrant compositioncomprising one or more disintegrants operable to disintegrate the tabletwithin a period of 2 minutes or less in contact with oral saliva.

Providing a fast disintegrating cannabinoid tablet according to theinvention may solve various problems of the prior art and aims atestablishing a formulation that combines beneficial delivery propertiesof cannabinoids combined with advantageous sensorics properties.

Generally, the tablet according to the invention disintegrates within arelatively short period of time without contributing significantly tooff notes from the cannabinoids released during use of the tablet. Thetablet is intended to disintegrate in the mouth without masticating,mainly with supply of saliva already present in the oral cavity orsaliva generation during use of the tablet. Hence, the tablet is neitherto be chewed nor to be swallowed but is to be kept in place in the mouthor swished forth and back in the mouth in the same way as a cleansingsystem for the oral cavity.

One of the attributes of the invention is the surprising recognitionthat it is possible to provide a tablet with fast disintegratingproperties and at the same time secure beneficial sensorial properties,including insignificant or less profound off note taste from thecannabinoids employed. The inventors of the applications did not expectthat a fast release of cannabinoids would be possible withoutcompromising the sensorial parameters of the tablet. The specialproperties of cannabinoids, such as CBD, was not considered to allow forsuch fast disintegration and release of the active ingredient. It isconsidered that cannabinoids as a diverse group of active ingredientsgenerally are subject to a prejudice within the art in terms of tasteproperties in oral tablet formulations. Also, the properties ofcannabinoids as a diverse group of active ingredients, such aslipophilic properties, would not have been expected to work properly insuch fast disintegrating tablets. In particular this includes CBD andCBDA. More particularly this includes extracts of cannabinoids, such asextracts of CBD and CBDA. Thus, in the art of cannabinoids a person ofordinary skill in the art would not expect that fast disintegratingtablets according to the invention would be feasible.

Specifically, the content of disintegrants greatly facilitatedisintegration of the tablet according to the invention. However, whiledisintegrants have previously been used in tablet formulation science,the particular combination of disintegrants with cannabinoids accordingto the application would have been seen as problematic in view of thespecific properties of cannabinoids, such as CBD. Various problems weresuspected by the inventors of the present application, such as sensorialdrawbacks and concentration issues with a high load of the activeingredients.

With respect to release properties, the present invention may offer animproved release profile of cannabinoids compared to conventionallozenge formulations. In particular, the specific tablet of the presentinvention may serve to provide improved release characteristics ofcannabinoids compared to conventional lozenge formulation platformsapplied in combination with cannabinoids. The improved release combinedwith the lipophilic characteristics of cannabinoids, such as CBD, wouldhave been expected to be contravening. However, the inventors recognizedthat delivery of cannabinoids were surprisingly beneficial.

In addition, the present invention may serve to provide fast andcontrolled release of cannabinoids such that the tablet formulation istailored to deliver an effective content of cannabinoids over time andat the same time avoid adverse effects of cannabinoids, such asoff-notes.

A very important aspect of the present invention is the provision ofbeneficial sensorics properties. Here, important sensorics propertiesinclude friability, texture, flavor perception, sweetness perception andoff-notes associated with cannabinoids. These properties are bothrelevant from a convenience perspective in tablets, but certainly alsoin order to support an appropriate delivery of cannabinoids from aformulation, such as an improved release profile, and avoid adverse sideeffects of cannabinoids.

The present inventors have shown very surprising results with thespecific combination of features of the present invention in terms ofthese sensorics properties. It was an unexpected result that theinvention could both contribute to an improved release profile, such asrapid release of cannabinoids, and at the same time provide verybeneficial sensorics properties which in terms may also support anappropriate delivery of cannabinoids from tablets with oral uptake andavoid adverse side effects of cannabinoids.

One of the sensorics properties that are particularly advantageous isfriability of the tablet. Both in order to secure a desired release ofcannabinoids and to improve the sensation by a consumer, it is criticalthat friability is balanced. Also, the texture of the tablet formulationduring use is critical for the release of cannabinoids and theexperience as well as convenience during use. These properties may beimproved by the present invention which was not expected by theinventors of the present invention.

Advantageously, the compositions of the present invention can beformulated in much smaller tablets than traditional cannabinoidcontaining lozenges and, thus, may have reduced dissolution times in theoral cavity while still achieving significant cannabinoid plasma leveland obtaining comparable cannabinoid pharmacokinetic profiles to thetraditional lozenge. By reducing dissolution time and improving thespeed of cannabinoid absorption, patient compliance may also beimproved.

In an embodiment of the invention, the one or more disintegrants isoperable to disintegrate the tablet within a period of 1.5 minutes orless in contact with oral saliva.

In an embodiment of the invention, the one or more disintegrants isoperable to disintegrate the tablet within a period of 1 minute or lessin contact with oral saliva.

In an embodiment of the invention, the one or more disintegrants isoperable to disintegrate the tablet within a period of 0.5 minute orless in contact with oral saliva.

In the present context, “operable” or “operable to disintegrate” isintended to mean that the tablet upon administration is able todisintegrate passively by means of saliva interaction and would not needto be masticated or otherwise forced to disintegrate. In otherembodiments, the tablet disintegrates within a period of 1.5 minutes orless in contact with oral saliva. In other embodiments, the tabletdisintegrates within a period of 1 minutes or less in contact with oralsaliva. In other embodiments, the tablet disintegrates within a periodof 0.5 minute or less in contact with oral saliva.

In the present context, “disintegrated” or “disintegrate” is intended tomean that the tablet is no longer to be considered a tablet but thetablet has been reduced and/or dispersed in saliva.

In the present context, the tablet is intended to mean a “fastdisintegrating tablet” (“FDT”), or similar wording, such as “orallydisintegrating tablet” (“ODT”). If not stated otherwise, if the tabletaccording to the invention is made as one module, contrary to two ormore modules, then the tablet is intended to be an FDT tablet. If on theother hand, the tablet is made of more than one module, such as twomodules, such additional module is intended to be a “lozenge” module,which provides a longer disintegration time compared to the FDT moduleaccording to the invention. The combination of a “FDT” module and a“lozenge” module is addressed later in this application and contributesto another aspect of the invention. A “lozenge” module according to theinvention may also comprise elements from the “FDT” modules but isgenerally different in composition, providing an extended disintegrationtime.

Importantly, the improved sensorics characteristics of the tabletformulation of the invention also accommodates an improved release rateof cannabinoids. The reason may be attributed to the fact that if theinitial impression by the user is improved and the tablet texture isalso improved, this would trigger the user to effectively use theproduct. Also, the production of saliva may be enhanced once the productformulation is improved, which in turn may accommodate further increasedrelease of cannabinoids. However, the precise mechanism is not wellunderstood.

Formulation of tablets according to the invention was seen to provide abeneficial disintegration compared to traditional tablet formulationsknown in the art. Surprisingly, it was seen that a disintegration timeof less than 30 seconds were possible without compromising theproperties of the tablet according to the invention. Sensorialproperties were only insignificantly or only to a less degree affectedby such a short period of disintegration time. Followingly, the fastdisintegrating tablets according to the invention may provide potentialrelatively quick alleviation or treatment response time.

In some embodiments of the invention, the composition in contact withsaliva has a disintegration profile that varies less than 10% under acompression pressure of 10 to 30 kN. In the present context“disintegration profile” is intended to mean that the weight percenttotal loss of material from the tablet for a given time during usevaries less than 10% under a tableting force from 10 to 30 kN. Themeasurement is generally measured while the tablet is not completely“disintegrated”. The measurement is taken while the tablet is in contactwith saliva as an in vivo measurement according to the measurementoutlined in the examples of the invention.

In an embodiment of the invention, the one or more disintegrants ispresent in an amount of 0.5 to 25% by weight of the tablet.

In some embodiments of the invention, the one or more disintegrants ispresent in an amount of 0.5 to 20% by weight of the tablet. In someembodiments of the invention, the one or more disintegrants is presentin an amount of 0.5 to 15% by weight of the tablet. In some embodimentsof the invention, the one or more disintegrants is present in an amountof 1 to 25% by weight of the tablet. In some embodiments of theinvention, the one or more disintegrants is present in an amount of 1 to20% by weight of the tablet.

In an embodiment of the invention, the one or more disintegrants ispresent in an amount of 2 to 15% by weight of the tablet.

In some embodiments of the invention, the one or more disintegrants ispresent in an amount of 2 to 10% by weight of the tablet. In someembodiments of the invention, the one or more disintegrants is presentin an amount of 3 to 15% by weight of the tablet. In some embodiments ofthe invention, the one or more disintegrants is present in an amount of4 to 15% by weight of the tablet. In some embodiments of the invention,the one or more disintegrants is present in an amount of 5 to 15% byweight of the tablet.

In an embodiment of the invention, the one or more disintegrants isswellable in contact with oral saliva. This implies that the tablet uponsaliva contact is broken into smaller pieces.

In an embodiment of the invention, the one or more disintegrantscomprises starch. This may in particular be the case when ready to usedisintegrant systems are employed, such as Pearlitol Flash that containsand amount of starch.

In an embodiment of the invention, the one or more disintegrantscomprises microcrystalline cellulose.

In an embodiment of the invention, the one or more disintegrantscomprises low-substituted hydroxypropyl cellulose (LHPC).

In an embodiment of the invention, the one or more disintegrantscomprises a super disintegrant. By “super disintegrant” the intendedmeaning is a disintegrant that provide a disintegrant effect that issuperior compared to more traditional disintegrant used in tabletmanufacture.

In an embodiment of the invention, the one or more disintegrantscomprises a super disintegrant in an amount of 2 to 15% by weight of thetablet.

In some embodiments of the invention, the one or more superdisintegrants is present in an amount of 2 to 10% by weight of thetablet. In some embodiments of the invention, the one or more superdisintegrants is present in an amount of 3 to 15% by weight of thetablet. In some embodiments of the invention, the one or more superdisintegrants is present in an amount of 4 to 15% by weight of thetablet. In some embodiments of the invention, the one or more superdisintegrants is present in an amount of 5 to 15% by weight of thetablet.

In an embodiment of the invention, the one or more disintegrantscomprises a super disintegrant of a cross-linked polymer.

In an embodiment of the invention, the one or more disintegrantscomprises a super disintegrant selected from the group consisting ofsodium croscarmellose, crospovidone, sodium starch glycolate andcombinations thereof.

In an embodiment of the invention, the one or more disintegrantscomprises cross-linked polyvinylpyrrolidone.

In an embodiment of the invention, the one or more disintegrantscomprises cross-linked polyvinylpyrrolidone and wherein at least 50% byweight of the cross-linked polyvinylpyrrolidone has a particle sizebelow 50 micrometers.

In an embodiment of the invention, the one or more disintegrantscomprises cross-linked polyvinylpyrrolidone and wherein at least 25% byweight of the cross-linked polyvinylpyrrolidone has a particle sizebelow 15 micrometers.

In an embodiment of the invention, the one or more solid particles arewater insoluble.

In an embodiment of the invention, the plurality of solid particles areselected from the group consisting of silica, microcrystallinecellulose, cellulose, silicified microcrystalline cellulose, clay, talc,starch, pregelatinized starch, calcium carbonate, dicalcium phosphate,magnesium carbonate, magnesium-alumino-metasilicates, hyper poroussilica and mixtures thereof. In some embodiments of the invention,silica is less preferred in the master granule component. In someembodiments of the invention, silica is to be avoided in the mastergranule component.

In an embodiment of the invention, the plurality of solid particlescomprise microcrystalline cellulose.

In an embodiment of the invention, the one or more solid particles arewater-soluble.

In an embodiment of the invention, the plurality of solid particlescomprise one or more sugar alcohols. In an embodiment of the invention,the solid particles comprise directly compressible (DC) sugar alcohols.In an embodiment of the invention, the solid particles comprisenon-directly compressible (non-DC) sugar alcohols.

In an embodiment of the invention, the one or more solid particles areselected from the group consisting of xylitol, lactitol, sorbitol,maltitol, erythritol, isomalt and mannitol, and mixtures andcombinations thereof.

In an embodiment of the invention, the one or more sugar alcoholparticles is present in an amount of at least 30% by weight of thetablet. In an embodiment of the invention, the one or more sugar alcoholparticles is present in an amount of at least 40% by weight of thetablet. In an embodiment of the invention, the one or more sugar alcoholparticles is present in an amount of at least 50% by weight of thetablet. In an embodiment of the invention, the one or more sugar alcoholparticles is present in an amount of at least 60% by weight of thetablet.

In an embodiment of the invention, the one or more sugar alcoholparticles is selected from the group consisting of xylitol, lactitol,sorbitol, maltitol, erythritol, isomalt and mannitol, and mixtures andcombinations thereof. In an embodiment of the invention, the one or moresugar alcohols are in free form.

In some embodiments of the invention, the content of sugar alcohol inthe composition is more than 70% by weight of the composition, such asmore than 80% by weight of the composition.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore solid materials, such as microcrystalline cellulose.

The solid component may serve to obtain a more homogeneous mixture ofcannabinoids in addition to the aforementioned benefits. However, due tothe nature of the materials, such as friability properties, it may insome embodiments be an advantage that the materials are only present inan amount less than the amount of free sugar alcohol particles. On theother hand, it may be an advantage to have a certain amount of thematerials combined with cannabinoids to secure a homogeneous mixture ofthe tablets.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with 1:10 to 1:4 by weight of theone or more sugar alcohol particles. In an embodiment of the invention,at least a part of the one or more cannabinoids is reversibly associatedwith 1:30 to 1:2 by weight of the one or more sugar alcohol particles.In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with 1:20 to 1:3 by weight of theone or more sugar alcohol particles.

In some embodiments of the invention, at least a part of the one or morecannabinoids is reversibly associated with 1:15 to 1:3 by weight of theone or more sugar alcohol particles. In some embodiments of theinvention, at least a part of the one or more cannabinoids is reversiblyassociated with 1:20 to 1:2 by weight of the one or more sugar alcoholparticles.

In the present context the wording “cannabinoids reversibly associatedwith the one or more solid particles” or “cannabinoids reversiblyassociated with the one or more sugar alcohol particles” or similarwording is intended to mean that the one or more cannabinoids are incontact with the one or more solid particles and are not looselydistributed within the material. During storage of the tabletcomposition and during storage of a tablet, the one or more cannabinoidsare generally associated with the one or more solid particles. This maybe in form of physical attachment, encapsulation, incorporation,solution, chemical interactions, or the like. However, during use in theoral cavity in contact with saliva, the intention is that thecannabinoids may be detached or released from the one or more solidparticles, so that the one or more cannabinoids may target mucosalsurfaces. The meaning of “reversibly” is therefore intended to mean thatthe one or more solid particles work as a means to carry the one or morecannabinoids before use and to secure delivery of the one or morecannabinoids. Also, the one or more solid particles may work to secure amicroenvironment that may provide a more stable composition.Furthermore, the one or more solid particles may secure that the one ormore cannabinoids are targeted to their site of action, i.e. the mucosalmembrane.

In an embodiment of the invention at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles by means of agglomeration. In an embodimentof the invention, the agglomeration is obtained through wet granulation.In an embodiment of the invention, the agglomeration is obtained throughdry granulation.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles by means of a plurality of granules with avolume weighted mean diameter of 10-400 μm.

Granules are preferred in some embodiments. A common problem associatedwith transmucosal administration via the buccal route is swallowing dueto the continuous secretion of saliva in the oral cavity. For optimaldrug delivery, the tablet formulation may preferably remain in contactwith oral mucosa for a time sufficient to allow for the absorption ofthe one or more cannabinoids. More specifically, tablet formulations maypreferably not be washed away by saliva into the gastrointestinal tractif buccal absorption is the target. However, the rate of disintegrationor dissolution of the tablet formulation may preferably not be so slowas to cause discomfort or inconvenience for the user. Additionally,suitable tablet formulations may preferably be small in size anddesigned so that the shape avoids discomfort to the patient during use.Most importantly the formulation may preferably be designed so that thecannabinoid is in a solution which optimizes its transmucosalpermeation. These considerations may be obtained with a premixture ofthe present invention.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles by means of a plurality of granules with avolume weighted mean diameter of 50-300 μm.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore solid particles by means of a premixture.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles by means of a premixture.

In the present context, a “premixture” or similar wording is intended tomean that the one or more cannabinoids have been mixed with the one ormore solid particles, such as solid sugar alcohol particles, prior tobeing applied in the tablet formulation together with the sugar alcoholformulation.

In the present context, a premixture is partly used to allocate the oneor more cannabinoids properly to the manufacturing process and securethat the uniformity is not compromised and that the cannabinoids aredistributed properly into the mixture. Preferably, the cannabinoids areprovided in a premixture with one or more sugar alcohols. It was asurprise to the inventors that a premixture was important to have inorder for the cannabinoids to be distributed properly in themanufacturing process and to end up with a product where the uniformitywas consistent.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles by means of adsorption in a premixture.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles by means of adsorption and wherein the oneor more cannabinoids is applied by spraying.

In an embodiment of the invention, the particles comprise one or morecannabinoid solvents into which the one or more cannabinoids aresolvated, such as glycol, alcohol or alkyl solvents or mixtures thereof.This may for instance be the case where an isolated cannabinoid isapplied, such as a solid isolated cannabinoid.

In an embodiment of the invention, the one or more cannabinoid solventsare selected from the group consisting of polyethylene glycol, ethanol,substituted polyethylene glycols, diethylene glycol monoethyl ether,propylene glycol, propylene carbonate, or a mixture thereof.

In an embodiment of the invention, the tablet is compressed at apressure of more than 10 kN. In an embodiment of the invention, thetablet is compressed at a pressure of more than 15 kN. In an embodimentof the invention, the tablet is compressed at a pressure of less than 30kN.

In an embodiment of the invention, at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles, reducing compressibility of thecomposition compared to a composition where the one or more cannabinoidsis not reversibly associated with at least a part of the one or moresugar alcohol particles.

In an embodiment of the invention, the tablet in contact with saliva hasa disintegration profile that varies less than 10% under a compressionpressure of 10 to 30 kN.

In an embodiment of the invention, the tablet in contact with saliva hasa disintegration profile that varies less than 5% under a compressionpressure of 10 to 30 kN.

In some embodiments of the invention, the composition in contact withsaliva has a disintegration profile that is substantially the same undera compression pressure of 10 to 30 kN.

One of the observations with great impact of the present invention isthat the compression force generally does not have a high influence onthe disintegration time of the tablets and even not on the dissolutiontime of the tablets. Common understanding in the art of tableting isthat the compression force has a huge influence on the disintegrationtime and dissolution time of tablets. The inventors have discovered thatthe present formulation of cannabinoids is very advantageous in thisaspect.

In an embodiment of the invention, the weight ratio of the one or morecannabinoids relative to the one or more sugar alcohol particles is from1:30 to 1:1. In an embodiment of the invention, the weight ratio of theone or more cannabinoids relative to the one or more sugar alcoholparticles is from 1:20 to 1:10.

In an embodiment of the invention, the tablet is further comprising abinder, such as a dry or wet binder.

In an embodiment of the invention, the tablet is further comprising atleast one dissolution modifier selected from the group consisting ofacacia, agar, alginic acid or a salt thereof, carbomer,carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone,cyclodextrins, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose,hypromellose, inulin, methylcellulose, pectin, polycarbophil or a saltthereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol,pullulan, starch, tragacanthin, trehalose, xanthan gum and mixturesthereof.

In an embodiment of the invention, the tablet is further comprising atleast one dissolution modifier selected from the group consisting ofalginic acid or a salt thereof, polycarbophil or a salt thereof, xanthangum and mixtures thereof.

In an embodiment of the invention, the tablet is further comprising atleast one dissolution modifier selected from the group consisting ofsodium alginate, calcium polycarbophil, xanthan gum and mixturesthereof.

In an embodiment of the invention, the tablet is further comprising atleast one viscolising agent that when hydrated forms a gel havingpositive surface electrical charge and at least one viscolising agentthat when hydrated forms a gel having negative surface electricalcharge.

In an embodiment of the invention, the tablet is further comprising atleast one alkaline buffering agent selected from the group consisting ofsodium carbonate, sodium bicarbonate, potassium phosphate, potassiumcarbonate and potassium bicarbonate, and mixtures thereof.

In an embodiment of the invention, the tablet is further comprising atleast one excipient selected from the group consisting of high intensitysweeteners, flavors, chelating agents, glidants or colorants.

In an embodiment of the invention, the unit weight of the tablet is fromabout 50 mg to about 250 mg. In an embodiment of the invention, the unitweight of the tablet is from about 75 mg to about 150 mg. This isparticularly the case when a tablet of only one module is made, such aswhen the tablet is a fast disintegrating tablet without any lozengemodules.

In an embodiment of the invention, the average particle size of thesugar alcohol composition is less than 350 micrometer. In an embodimentof the invention, the average particle size of the sugar alcoholcomposition is less than 250 micrometer. In an embodiment of theinvention, the average particle size of the sugar alcohol composition isat least 100 micrometer.

In an embodiment of the invention, the one or more cannabinoids ispresent in an amount of 0.5 to 100 mg.

In an embodiment of the invention, the one or more cannabinoids ispresent in an amount of 1 to 80 mg. In an embodiment of the invention,the one or more cannabinoids is present in an amount of 5 to 50 mg. Inan embodiment of the invention, the one or more cannabinoids is presentin an amount of 5 to 30 mg. In an embodiment of the invention, the oneor more cannabinoids is present in an amount of 5 to 20 mg.

In some embodiments of the invention, the unit weight of the tabletcomposition is from about 50 mg to about 2000 mg. In some embodiments ofthe invention, the unit weight of the tablet composition is from about50 mg to about 1000 mg. In some embodiments of the invention, the unitweight of the tablet composition is from about 50 mg to about 750 mg. Insome embodiments of the invention, the unit weight of the tabletcomposition is from about 100 mg to about 750 mg. This is particularlythe case when a tablet of two or more modules is made, such as when thetablet comprises a fast disintegrating module and a lozenge module.

In some embodiments of the invention, the one or more cannabinoids arepresent in an amount of 0.1 to 400 mg. In some embodiments of theinvention, the one or more cannabinoids are present in an amount of 10to 100 mg.

In an embodiment of the invention, the one or more cannabinoids arepresent in an amount of 0.1 to 200 mg. In some other embodiments of theinvention, the one or more cannabinoids are present in an amount of 0.1to 100 mg. In some other embodiments of the invention, the one or morecannabinoids are present in an amount of 0.1 to 50 mg. In an embodimentof the invention said tablet comprises said cannabinoids in an amount of0.1-30 mg, such as 1-20 mg, such as 5-15 mg.

In an embodiment of the invention, the one or more cannabinoidscomprises cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin(CBDV), salts and derivatives thereof.

In an embodiment of the invention, the one or more cannabinoidscomprises tetrahydrocannabinol (THC), tetrahydrocannabinolic acid(THCA), tetrahydrocannabivarin (THCV), salts and derivatives thereof.

In an embodiment of the invention, the one or more cannabinoidscomprises cannabidiol (CBD).

In an embodiment of the invention, the one or more cannabinoids isselected from the group consisting of cannabidiol (CBD), cannabidiolicacid (CBDA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid(THCA), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN),cannabielsoin (CBE), iso-tetrahydrocannabinol (iso-THC), cannabicyclol(CBL), cannabicitran (CBT), cannabivarin (CBV), tetrahydrocannabivarin(THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV),cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), saltsthereof, derivatives thereof and mixtures of cannabinoids.

In an embodiment of the invention, the one or more cannabinoids comprisecannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV),salts and derivatives thereof. In an embodiment of the invention the oneor more cannabinoids comprises CBD, salts and derivatives thereof,including analogues and homologues. In an embodiment of the inventionsaid one or more cannabinoids comprises CBD. In an embodiment of theinvention said one or more cannabinoids is CBD.

In an embodiment of the invention, the one or more cannabinoids comprisetetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV), salts and derivatives thereof. In anembodiment of the invention said one or more cannabinoids comprisestetrahydrocannabinol (THC). Preferably THC is intended to mean(-)-trans-Δ⁹-tetrahydrocannabinol, i.e.(6aR,10aR)-delta-9-tetrahydrocannabinol). In an embodiment of theinvention said one or more cannabinoids is THC.

In an embodiment of the invention, the one or more cannabinoids compriseat least two cannabinoids. In an embodiment of the invention said one ormore cannabinoids comprises a combination of several cannabinoids, suchas THC and CBD. In an embodiment of the invention said one or morecannabinoids is a combination of THC and CBD.

In an embodiment of the invention, the tablet formulation comprisesflavor in an amount between 0.01 and 10% by weight of the tabletformulation such as in an amount between 0.01 and 5% by weight of thetablet formulation.

In an embodiment of the invention, the tablet formulation comprises highintensity sweetener.

In an embodiment of the invention, the one or more cannabinoids arepresent in solid form. In an embodiment of the invention, the one ormore cannabinoids are present in liquid or semi-liquid form.

In an embodiment of the invention, the one or more cannabinoids formspart of a complex with cyclodextrin. In an embodiment of the invention,the one or more cannabinoids form part of a complex with cyclodextrin.This complex may enhance the release of cannabinoids according to thepresent invention. Also, the complex may enhance delivery of the one ormore cannabinoids to the oral mucosa.

In an embodiment of the invention, the one or more cannabinoidscomprises at least one phytocannabinoid that forms part of an extract.In some embodiments of the invention, it was seen that cannabinoids aspart of an extract may enhance the release of cannabinoids.

In an embodiment of the invention, the one or more cannabinoidscomprises at least one isolated cannabinoid.

In an embodiment of the invention, the one or more cannabinoids islocated in a protein carrier, such as pea protein carrier.

In an embodiment of the invention, the one or more cannabinoids islocated in a polymer carrier.

In an embodiment of the invention, the one or more cannabinoids islocated in an amphiphilic polymer carrier.

In an embodiment of the invention, the one or more cannabinoidscomprises at least one endocannabinoid or endocannabinoid-like compound,such as palmitoylethanolamide (PEA).

In an embodiment of the invention, the one or more cannabinoidscomprises at least one water-soluble cannabinoid.

In an embodiment of the invention, the tablet comprises aself-emulsifying agent.

In an embodiment of the invention, the tablet comprises a lipophilicassociation between the one or more cannabinoids and a fatty acid, suchas oleic acid.

In an embodiment of the invention, the tablet comprises a lipid carrierfor the one or more cannabinoids.

In an embodiment of the invention, the one or more cannabinoid lipidcarriers comprises one or more terpenes.

In an embodiment of the invention, the one or more cannabinoid lipidcarriers comprises one or more terpenes selected from the groupconsisting of bisabolol, borneol, caryophyllene, carene, camphene,cineol, citronella, eucalyptol, geraniol, guaiol, humulene,isopropyltoluene, isopulegol, linalool, limonene, menthol, myrcene,nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpinolene,thymol, salts thereof, derivatives thereof, and mixtures of terpenes.

In an embodiment of the invention, the tablet is used for the treatmentor alleviation of a medical condition.

In certain embodiments of the invention, the tablet formulation of thepresent invention may be used for the treatment or alleviation of amedical condition selected from the group consisting of pain, epilepsy,cancer, nausea, inflammation, congenital disorders, neurologicaldisorders, oral infections, dental pain, sleep apnea, psychiatricdisorders, gastrointestinal disorders, inflammatory bowel disease,appetite loss, diabetes and fibromyalgia.

In another aspect of the invention, the tablet comprises a furthertablet module that is different in composition.

If not stated otherwise, if the tablet according to the invention ismade as one module, contrary to two or more modules, then the tablet isintended to be an FDT tablet. If on the other hand, the tablet is madeof more than one module, such as two modules, such additional module isintended to be a “lozenge” module, which provides a longerdisintegration time compared to the FDT module according to theinvention. The combination of a “FDT” module and a “lozenge” module isaddressed in the following sections and contributes to another aspect ofthe invention. A “lozenge” module according to the invention may alsocomprise elements from the “FDT” modules described in the previoussections but is generally different in composition, providing anextended disintegration time.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and comprises one or morecannabinoids according to the previous description of FDT elements.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and disintegrates within aperiod of 3 minutes or more in contact with oral saliva

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and disintegrates within aperiod of 4 minutes or more in contact with oral saliva

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and comprises a sugar alcoholcomposition according to the previous description of FDT elements.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and comprising a sugar alcoholcomposition having a larger average particle size.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and constitutes at least 50% byweight of the total tablet.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and constitutes at least 60% byweight of the total tablet.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and constitutes at least 70% byweight of the total tablet.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and constitutes between 50-90%by weight of the total tablet.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and constitutes between 60-90%by weight of the total tablet.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and constitutes between 70-90%by weight of the total tablet.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and having a unit weight fromabout 250 mg to about 950 mg.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and having a unit weight fromabout 400 mg to about 900 mg.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and having a unit weight fromabout 400 mg to about 900 mg.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and having a unit weight fromabout 200 mg to about 500 mg.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and comprises gum base polymers.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and does not comprise gum basepolymers.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and is tableted together with anFDT tablet according to the previous description of FDT elements, toform an integrated two-layered tablet.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and is tableted in a separatestep before tableting the FDT tablet according to the previousdescription of FDT elements.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and is tableted in a separatestep with a higher pressure before tableting the FDT tablet according tothe previous description of FDT elements.

In an embodiment of the invention, the tablet comprises a further tabletmodule that is different in composition and comprises any of a binder, adissolution agent, an excipient, a viscolising agent or an alkalinebuffering agent according to the previous description of FDT elements.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in more details with respect tocertain aspects and embodiments of the invention. These aspects andembodiments are intended to be understood in connection with the rest ofthe description, including the Summary of the Invention and the Examplesof the invention.

As used herein, the term “approximately” or “about” in reference to anumber are generally taken to include numbers that fall within a rangeof 5%, 10%, 15%, or 20% in either direction (greater than or less than)of the number unless otherwise stated or otherwise evident from thecontext (except where such number would be less than 0% or exceed 100%of a possible value).

As used herein, the term “disintegrate” refers to a reduction of anobject to components, fragments or particles. Disintegration time may bemeasured in vitro or in vivo. Unless otherwise stated, the in vitromeasurements are carried out in accordance to European Pharmacopeia 9.0,section 2.9.1, Disintegration of tablets and capsules.

As used herein, the term “dissolve” is the process where a solidsubstance enters a solvent (oral saliva) to yield a solution. Unlessotherwise stated, dissolving implies a full dissolving of the compoundin question.

As used herein, the terms “disintegrant” refers to an ingredientfacilitating disintegration of an FDT-module, when the FDT-module comesinto contact with saliva. Disintegrants usable within the scope of theinvention may include starch, pregelatinated starch, modified starch(including potato starch, maize starch, starch 1500, sodium starchglycolate and starch derivatives), cellulose, microcrystallinecellulose, alginates, ion-exchange resin, and superdisintegrants, suchas crosslinked cellulose (such as sodium carboxy methyl cellulose),crosslinked polyvinyl pyrrolidone (PVP), crosslinked starch, crosslinkedalginic acid, natural superdisintegrants, and calcium silicate.Disintegrants may often be considered as measure promoting the break-upof the module into smaller fragments upon administration to facilitatenicotine release and eventual absorption. Crospovidone may comprisevarious grades, such as Kollidon CL-F or Kollidon CL-SF available fromBASF.

The term “disintegrant composition” is intended to mean a volume ofmatter comprising one or more disintegrant. The disintegrant compositionmay contain other excipients than disintegrants. The disintegrantcomposition may constitute disintegrants. The disintegrant compositionmay constitute one type of disintegrants. The disintegrant compositionmay constitute two types of disintegrants. The disintegrant compositionmay constitute two or more types of disintegrants. Preferably, thedisintegrant composition comprises a “portion of particles”. Preferably,the disintegrant composition is a “portion of particles”.

The term “particle size” relates to the ability of the particles to movethrough or be retained by sieve holes of a specific size. As usedherein, the term “particle size” refers to the average particle size asdetermined according to European Pharmacopoeia 9.1 when using testmethod 2.9.38 particle size distribution estimation by analyticalsieving, unless otherwise specifically is mentioned.

The term “plurality of particles” is intended to cover the “populationof particles” in the sense that the sum of populations are covered bythe term “plurality”.

The term “portion of particles” or similar wording is intended to mean aplurality of particles that collectively may comprise one or morepopulations of particles.

The term “particle” or similar wording is intended to denote a single,discrete composition of solid matter, such as a granule or individualelements in powder, having a certain size that may deviate considerable.

The term “DC sugar alcohol particles” or similar wording refers toparticles of direct compressible (DC) sugar alcohol. DC sugar alcoholparticles may be obtained e.g. as particles of sugar alcohols having DCgrade by nature, e.g. sorbitol, or by granulating non-DC sugar alcoholwith e.g. other sugar alcohols or binders for the purpose of obtainingso-called direct compressible particles (DC). Also, granulation ofnon-DC sugar alcohol with water as binder is considered to result in “DCsugar alcohol particles” in the present context. This is contrary to theterm “non-DC sugar alcohol particles” that refers to particles ofnon-directly compressible (non-DC) sugar alcohol. In the presentcontext, the non-DC sugar alcohol particles refer to particles whichhave not been preprocessed by granulation with e.g. other sugar alcoholsor binders for the purpose of obtaining so-called direct compressibleparticles (DC). Thus, non-DC sugar alcohol particles are considered asparticles consisting of non-DC sugar alcohol.

The term “sugar alcohol composition” is intended to mean a volume ofmatter comprising one or more sugar alcohols. The disintegrantcomposition may contain other excipients than sugar alcohols. The sugaralcohol composition may constitute sugar alcohols. The sugar alcoholcomposition may constitute one type of sugar alcohols. The sugar alcoholcomposition may constitute two types of sugar alcohols. The sugaralcohol composition may constitute two or more types of sugar alcohols.Preferably, the sugar alcohol composition comprises a “portion ofparticles”. Preferably, the sugar alcohol composition is a “portion ofparticles”.

The term “tableted” or “tablet” or “compressed” is intended to mean thatthe tablet composition is pressed in a tableting apparatus and mainlybeing composed of particulate matter. Although the terms imply a methodstep, in the present context, the terms are intended to mean theresulting tablet obtained in tableting a portion of particles. It isnoted that a tablet or tableted composition that is mentioned tocomprise particles eventually is to be understood as particles that havebeen pressed together in a tableting step.

In one aspect of the invention, the “tablet” is intended to mean a “fastdisintegrating tablet” (“FDT”), or similar wording, such as “orallydisintegrating tablet” (“ODT”). If not stated otherwise, if the tabletaccording to the invention is made as one module, contrary to two ormore modules, then the tablet is intended to be an FDT tablet. If on theother hand, the tablet is made of more than one module, such as twomodules, such additional module is intended to be a “lozenge” module,which provides a longer disintegration time compared to the FDT moduleaccording to the invention. The combination of an “FDT” module and a“lozenge” module contributes to another aspect of the invention. A“lozenge” module according to the invention may also comprise elementsfrom the “FDT” modules but is generally different in composition,providing an extended disintegration time.

The term “lozenge” is intended to cover that a “lozenge composition” hasbeen “compressed” into a “lozenge module”. In the present context, a“lozenge module” or similar wording is intended to mean that the moduleduring use in the oral cavity is intended to be sucked or licked on. Theterm “lozenge” is given the ordinary meaning in the art of lozenges. Theintention is that the lozenge module may not be chewed. The intention isalso that the FDT module may not be chewed. Generally, the “lozengemodule” of the present invention may disintegrate upon sucking or lickedin minutes, contrary to seconds for orally disintegrating tablets (ODT)or fast disintegrating tablets (FDT) tablets. Hence, the intention isthat the “lozenge module” is to deliver the one or more cannabinoidsover a longer period of time than the FDT module, if the tablet is madeas a combination of the two modules.

The term “module” is generally intended to be composed of a compositionof matter with substantially the same characteristics throughout themodule. Hence, if two module are present, then the two modules aredifferent in composition and generally have two differentcharacteristics throughout each module. In the present context, if onlyone module is present, then this module is considered an FDT tablet. Onthe other hand, if two modules are present, then the tablet is composedof an FDT tablet or FDT tablet module fused with a lozenge tablet orlozenge module. The term “fused” is intended to mean that the tablet isgathered together by means of compression force. Usually, if two modulesare present, the lozenge module is made as the first module and the FDTmodule is made as the second module. The tablet may be composed of morethan two module. The lozenge module may in certain embodiments bereplaced by a gum base module. In the present context, the inventionprovides an attractive bi-phasic delivery of masking, even if thedelivery of nicotine is “single-phased”.

The wording “a further tablet module that is different in composition”or similar wordings is intended to mean that this further module isdistinguished from the FDT module in the sense that the composition ofthe module is substantially different from the FDT module, such as withrespect to disintegration time.

The term “cannabinoid composition” is intended to mean a volume ofmatter comprising one or more cannabinoids. The cannabinoid compositionmay contain other components than cannabinoids. The cannabinoidcomposition may constitute cannabinoids. The cannabinoid composition mayconstitute one type of cannabinoids. The cannabinoid composition mayconstitute two types of cannabinoids. The cannabinoid composition mayconstitute two or more types of cannabinoids.

The term “weight of the tablet composition” or similar wording meaningthe same is defined in the present context as weight of the tabletcomposition, not including the weight of an outer coating, such as ahard coating, soft coating, and the like.

By the phrase “texture” is meant a qualitative measure of the propertiesof the tablet composition or tablet and of the overall mouth feelexperienced by the user during use. Thus, the term “texture” encompassesmeasurable quantities such as hardness as well as more subjectiveparameters related to the feel experienced by a user.

The term “in vivo use” intends to mean that the tablet compositionsystem is used by a human subject in an experimental setup of trainedtest persons according to statistically principles and that either thesaliva of the human subject is subject to measurements or the tabletcomposition is subject to measurements.

The term “in vivo release” or “in vivo testing of release” or similarwording intends to mean that the tablet composition is tested asoutlined in the examples.

The term “in vitro release” or “in vitro testing of release” or similarwording intends to mean that the tablet composition is tested accordingto the examples.

The term “release” in the present context is intended to mean under “invitro” conditions if not stated otherwise. In particular, the “releaserate” during a certain period of time is intended to mean the amount inpercentage of cannabinoids that is released during the period.

The term “sustained release” or “extended release” is herein intended tomean prolonged release over time. The term “rapid release” or “quickrelease” or “high release” is herein intended to mean a higher contentreleased for a given period of time. The term “controlled release” isintended to mean a release of a substance from a tablet composition bythe aid of active use of the tablet composition in the oral cavity ofthe subject, whereby the active use is controlling the amount ofsubstance released.

The term “delivery to the oral mucosa” or similar wording intends tomean that the tablet composition is tested according to the examples.

As used herein, the term “buffering agent” is used interchangeably with“buffer” and refers to agents for obtaining a buffer solution. Bufferingagents include acidic buffering agents, i.e. for obtaining a buffersolution with an acidic pH, and alkaline buffering agents, i.e. forobtaining a buffer solution with an alkaline pH.

A “self-emulsifying agent” is an agent which will form an emulsion whenpresented with an alternate phase with a minimum energy requirement. Incontrast, an emulsifying agent, as opposed to a self-emulsifying agent,is one requiring additional energy to form an emulsion.

In an embodiment of the invention, the tablet composition comprisesfurther tablet composition ingredients selected from the groupconsisting of flavors, dry-binders, tableting aids, anti-caking agents,emulsifiers, antioxidants, enhancers, mucoadhesives, absorptionenhancers, high intensity sweeteners, softeners, colors, activeingredients, water-soluble indigestible polysaccharides, water-insolublepolysaccharides or any combination thereof.

In embodiments where the lozenge comprises fillers, different fillersmay be used. Microcrystalline cellulose may be used as a filler in someembodiments of the invention. Examples of usable fillers includemagnesium- and calcium carbonate, sodium sulphate, ground limestone,silicate compounds such as magnesium- and aluminum silicate, kaolin andclay, aluminum oxide, silicium oxide, talc, titanium oxide, mono-, di-and tri-calcium phosphates, cellulose polymers, such as wood, starchpolymers, fibers and combinations thereof.

Examples of usable disintegrants include starch, pregelatinated starch,modified starch (including potato starch, maize starch, starch 1500,sodium starch glycolate and starch derivatives), cellulose,microcrystalline cellulose, alginates, ion-exchange resin, andsuperdisintegrants, such as crospovidone, croscarmellose sodium, andsodium starch glycolate, crosslinked cellulose (such as sodium carboxymethyl cellulose), crosslinked polyvinyl pyrrolidone (PVP), crosslinkedstarch, crosslinked alginic acid, natural superdisintegrants, andcalcium silicate, and combinations thereof.

Usable high intensity sweeteners include, but are not limited tosucralose, aspartame, salts of acesulfame, such as acesulfame potassium,alitame, saccharin and its salts, cyclamic acid and its salts,glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside and thelike, alone or in combination.

Usable flavors include almond, almond amaretto, apple, Bavarian cream,black cherry, black sesame seed, blueberry, brown sugar, bubblegum,butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake(graham crust), cinnamon redhots, cotton candy, circus cotton candy,clove, coconut, coffee, clear coffee, double chocolate, energy cow,graham cracker, grape juice, green apple, Hawaiian punch, honey,Jamaican rum, Kentucky bourbon, kiwi, koolada, lemon, lemon lime,tobacco, maple syrup, maraschino cherry, marshmallow, menthol, milkchocolate, mocha, Mountain Dew, peanut butter, pecan, peppermint,raspberry, banana, ripe banana, root beer, RY 4, spearmint, strawberry,sweet cream, sweet tarts, sweetener, toasted almond, tobacco, tobaccoblend, vanilla bean ice cream, vanilla cupcake, vanilla swirl, vanillin,waffle, Belgian waffle, watermelon, whipped cream, white chocolate,wintergreen, amaretto, banana cream, black walnut, blackberry, butter,butter rum, cherry, chocolate hazelnut, cinnamon roll, cola, creme dementhe, eggnog, English toffee, guava, lemonade, licorice, maple, mintchocolate chip, orange cream, peach, pina colada, pineapple, plum,pomegranate, pralines and cream, red licorice, salt water taffy,strawberry banana, strawberry kiwi, tropical punch, tutti frutti,vanilla, or any combination thereof.

Usable buffering agents include carbonate, including monocarbonate,bicarbonate and sesquicarbonate, glycerinate, phosphate,glycerophosphate, acetate, glyconate or citrate of an alkali metal,ammonium, tris buffer, amino acids and mixtures thereof. Encapsulatedbuffer such as Effersoda may also be used.

In some embodiments, the buffering agent comprises sodium carbonate andsodium bicarbonate, e.g. in a weight-ratio between 5:1 and 2.5:1,preferably in a weight-ratio between 4.1:1 and 3.5:1.

Silicon dioxide may be used as a glidant. Other glidants usable for theformulation may also be used within the scope of the invention.Magnesium stearate and/or sodium stearyl fumerate may be used as alubricant. Other lubricants usable for the formulation may also be usedwithin the scope of the invention.

Ready to use systems may be used within the scope of the invention.Typically, such ready-to-use systems may e.g. replace filler,disintegrant, glidant or similar with a single powder mix. Suitableready-to-use systems for the purpose, but not limited to, includePearlitol Flash (Roquette), Pharmaburst 500 (SPI Pharma), Ludiflash(BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-Melt (FujiChemical), SmartEx50 or SmartEx100 (Shin Etsu/Harke Pharma). Using aready to use systems comprising a disintegrant may be especiallyadvantageous.

Particularly, including a disintegrant may significantly influence thedisintegration time, subject to the total composition of the secondmodule. Also, by varying the amount and type of the disintegrant, thedisintegration time may be further adjusted. For example, if the secondlayer having a lower disintegration time is desired, the percentagecontent of disintegrant may be increased and/or the type of disintegrantmay be at least partly exchanged for a more effective disintegrant.

Also, decreasing the particle size of the disintegrant tends to lowerthe disintegration time, likely due to an increased surface area tovolume ratio.

Furthermore, the compression force used to press the second modulecorrelate significantly with the obtained hardness of the second module,such that a high compression force typically increases the hardness ofthe obtained second module. By adjusting the hardness of a secondmodule, the disintegration time may also be influenced, such that alowered hardness typically gives a shorter disintegration time. Here ithas been observed for a number of compositions that by applying thecorrect compression force a disintegration time below 60 seconds uponoral administration can be achieved, whereas a too high compressionforce may result in a longer disintegration time above 60 seconds. Inthis regard it is noted that the threshold compression force may varysignificantly, depending on other parameters, such as overallcomposition, content and type of disintegrant, etc. When, for example, acertain setup results in a too slow disintegration, a further way ofadjusting may be to replace a regular disintegrant with asuperdisintegrant, i.e. which facilitates disintegration in a moreefficient way.

Typically, the formulation of the FDT module may comprise ingredientsselected from the group consisting of bulk sweeteners, fillers, ready touse systems, flavors, dry-binders, disintegrant, hereundersuperdisintegrants, tabletting aids, anti-caking agents, emulsifiers,antioxidants, enhancers, absorption enhancers, buffering agents, highintensity sweeteners, colors, glidants, lubricants, or any combinationthereof. Absorption enhancers may include e.g. pH regulating agents,such as buffering agents, and mucoadhesive.

Mannitol may be used as the sugar alcohol in the lozenge module and FDTmodule. Particularly preferred mannitol grades include mannitol 100 SD,mannitol 150 SD or mannitol 200 SD commercially available from Roquettewith different average particle sizes. Other usable sugar alcohols foruse in the lozenge module may include sorbitol, erythritol, xylitol,maltitol, lactitol, and isomalt. Of these isomalt, erythritol, andsorbitol are particularly preferred. Other usable sugar alcohols for usein the FDT module may include sorbitol, erythritol, xylitol, maltitol,lactitol, and isomalt. The disintegrant in FDT module may e.g. be astarch based disintegrant. In embodiments of the invention, thedisintegrant may be supplied as part of a ready to use system, e.g.Pearlitol Flash from Roquette, a mannitol-based product comprisingapproximately 17% by weight of disintegrant. Examples of other usableready to use system include e.g. Pharmaburst 500 (SPI Pharma), Ludiflash(BASF), ProSolv (JRS Pharma), ProSolv EasyTab (JRS Pharma), F-Melt (FujiChemical), SmartEx50 or SmartEx100 (Shin Etsu/Harke Pharma).

Pearlitol Flash is used comprising approximately 17% by weight of starchdisintegrant. Examples of other usable ready to use system include e.g.Pharmaburst 500 (SPI Pharma), Ludiflash (BASF), ProSolv (JRS Pharma),ProSolv EasyTab (JRS Pharma), F-Melt (Fuji Chemical), SmartEx50 orSmartEx100 (Shin Etsu/Harke Pharma).

Preferred high intensity sweeteners (HIS) may e.g. be sucralose,acesulfame potassium, and mixtures thereof. Other high intensitysweeteners, such as aspartame, salts of acesulfame, such as acesulfamepotassium, alitame, saccharin and its salts, cyclamic acid and itssalts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside,alone or in combination, are also usable within the scope of theinvention.

Menthol, peppermint, and mixtures thereof may be used in the aboveformulations as flavors. Other flavors may also be used within the scopeof the invention.

Sodium carbonate may be used as the buffer. Further usable buffersinclude other carbonates, including monocarbonates, bicarbonates andsesquicarbonates, glycerinate, phosphate, glycerophosphate, acetate,glyconate or citrate of an alkali metal, ammonium, tris buffer, aminoacids and mixtures thereof.

In the above MgSt (Magnesium stearate) is used as lubricant. Otherlubricants, such as sodium stearyl fumerate may also be usable withinthe scope of the invention.

According to embodiments of the invention, emulsifiers may be selectedfrom the group consisting of sucrose ester of fatty acids (such assucrose mono stearate), polyethylene glycol esters or ethers (PEG) (suchas caprylocaproyl macrogol-8 glycerides and lauroylmacrogol-32-glycerides), mono- and diglyceride of fatty acids (such asglycerol monostearate, glycerol monolaurate, glyceryl behenate ester),acetic acid esters of mono- and diglycerides of fatty acids (Acetem),polyoxyethylene alkyl ethers, diacetyl tartaric ester of monoglycerides,lactylated monoglycerides, glycerophospholipids (such as lecithin),poloxamer (non-ionic block copolymer of ethylene oxide and propyleneoxide), cyclodextrins, fatty acid esters of sorbitol (such as sorbitanmonolaurate, sorbitan monostearate, sorbitan tristearate, polysorbates).Self-emulsifying emulsifiers may be phospholipids (Lecithin),Polysorbates (polysorbate 80).

SEDDS (self-emulsifying drug delivery system) may consist of hard orsoft capsules filled with a liquid or a gel that consists ofself-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids) and a surfactant. SEDDS may comprise of a blend or mixtureof self-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids) and a surfactant. SEDDS may comprise granules comprisingself-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids), one or more surfactants, solvent and co-solvents. Uponcontact with gastric fluid, the SEDDS spontaneously emulsify due to thepresence of surfactants. Many surfactants, however, are lipid based andinteract with lipases in the GIT (gastro intestinal tract). This canlead to a reduced capability of the lipid-based surfactants to emulsifythe one or more cannabinoids as well as the oil carrier, both reducingbioavailability.

In the present context, SEDDS is a solid or liquid dosage formcomprising an oil phase, a surfactant and optionally a co-surfactant,characterized primarily in that said dosage form can form oil-in-wateremulsion spontaneously in the oral cavity or at ambient temperature(referring generally to body temperature, namely 37° C.) with mildstirring. When a SEDDS enters the oral cavity, it is initiallyself-emulsified as emulsion droplets and rapidly dispersed throughoutthe oral cavity, and thus reducing the irritation caused by the directcontact of the drug with the mucous membrane of the oral cavity. In theoral cavity, the structure of the emulsion microparticulate will bechanged or destroyed. The resulting microparticulate of micrometer ornanometer level can penetrate into the mucous membrane of the oralcavity, and the digested oil droplets enter the blood circulation,thereby significantly improving the bioavailability of the drug.

Particularly with respect to SEDDS, the formulation of the presentinvention may provide some clear benefits, both allowing a higher loadof cannabinoids and at the same time offer improved sensorics propertiesof the formulation during use. Other advantages are also present.Compared to prior art formulations, it is believed that the combinationof the component where the one or more cannabinoids are associated andthe composition comprising one or more sugar alcohol particles providesthe benefits of the present invention both with respect to loading ofcannabinoids and improved sensorics properties, such as less off-notes.

In an embodiment of the invention, the one or more self-emulsifiers areselected from the group consisting of PEG-35 castor oil, PEG-6 oleoylglycerides, PEG-6 linoleoyl glycerides, PEG-8 caprylic/capric glyceride,sorbitan monolaurate, sorbitan monooleate, polyoxyethylene (20) sorbitanmonolaurate, polyoxyethylene (60) sorbitan monostearate, polyoxyethylene(80) sorbitan monooleate, lauroylpoloxyl-32 glycerides, stearoylpolyoxyl-32 glycerides, polyoxyl-32 stearate, propylene glycol monolaurate, propylene glycol di laurate, and mixtures and combinationsthereof.

According to embodiments of the invention, flavors may be selected fromthe group consisting of coconut, coffee, chocolate, vanilla, grapefruit, orange, lime, menthol, liquorice, caramel aroma, honey aroma,peanut, walnut, cashew, hazelnut, almonds, pineapple, strawberry,raspberry, tropical fruits, cherries, cinnamon, peppermint, wintergreen,spearmint, eucalyptus, and mint, fruit essence such as from apple, pear,peach, strawberry, apricot, raspberry, cherry, pineapple, and plumessence. The essential oils include peppermint, spearmint, menthol,eucalyptus, clove oil, bay oil, anise, thyme, cedar leaf oil, nutmeg,and oils of the fruits mentioned above.

Petroleum waxes aid in the curing of the finished tablet compositionmade from the tablet composition as well as improve shelf life andtexture. Wax crystal size influences the release of flavor. Those waxeshigh in iso-alkanes have a smaller crystal size than those waxes high innormal-alkanes, especially those with normal-alkanes of carbon numbersless than 30. The smaller crystal size allows slower release of flavorsince there is more hindrance of the flavor's escape from this waxversus a wax having larger crystal sizes.

Petroleum wax (refined paraffin and microcrystalline wax) and paraffinwax are composed of mainly straight-chained norm al-alkanes and branchediso-alkanes. The ratio of normal-alkanes to iso-alkanes varies.

Microcrystalline cellulose may be applied in various grades, such asAvicel PH-101, Avicel PH-102 or Avicel PH-105 commercially availablefrom FMC.

Antioxidants prolong shelf life and storage of tablet composition,finished tablet composition or their respective components includingfats and flavor oils.

Antioxidants suitable for use in tablet composition include butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), betacarotenes,tocopherols, acidulants such as Vitamin C (ascorbic acid orcorresponding salts (ascorbates)), propyl gallate, catechins, othersynthetic and natural types or mixtures thereof.

Further tablet composition ingredients, which may be included in thetablet composition according to the present invention, includesurfactants and/or solubilizers. As examples of types of surfactants tobe used as solubilizers in a tablet composition according to theinvention, reference is made to H.P. Fiedler, Lexikon der Hilfstoffe fürPharmacie, Kosmetik and Angrenzende Gebiete, pages 63-64 (1981) and thelists of approved food emulsifiers of the individual countries. Anionic,cationic, amphoteric or non-ionic solubilizers can be used. Suitablesolubilizers include lecithin, polyoxyethylene stearate, polyoxyethylenesorbitan fatty acid esters, fatty acid salts, mono and diacetyl tartaricacid esters of mono and diglycerides of edible fatty acids, citric acidesters of mono and diglycerides of edible fatty acids, saccharose estersof fatty acids, polyglycerol esters of fatty acids, polyglycerol estersof interesterified castor oil acid (E476), sodium stearoyllatylate,sodium lauryl sulfate and sorbitan esters of fatty acids andpolyoxyethylated hydrogenated castor oil (e.g. the product sold underthe trade name CREMOPHOR), block copolymers of ethylene oxide andpropylene oxide (e.g. products sold under trade names PLURONIC andPOLOXAMER), polyoxyethylene fatty alcohol ethers, polyoxyethylenesorbitan fatty acid esters, sorbitan esters of fatty acids andpolyoxyethylene steraric acid esters.

Particularly suitable solubilizers are polyoxyethylene stearates, suchas for instance polyoxyethylene(8)stearate andpolyoxyethylene(40)stearate, the polyoxyethylene sorbitan fatty acidesters sold under the trade name TWEEN, for instance TWEEN 20(monolaurate), TWEEN 80 (monooleate), TWEEN 40 (monopalmitate), TWEEN 60(monostearate) or TWEEN 65 (tristearate), mono and diacetyl tartaricacid esters of mono and diglycerides of edible fatty acids, citric acidesters of mono and diglycerides of edible fatty acids, sodiumstearoyllatylate, sodium laurylsulfate, polyoxyethylated hydrogenatedcastor oil, blockcopolymers of ethylene oxide and propyleneoxide andpolyoxyethylene fatty alcohol ether. The solubilizer may either be asingle compound or a combination of several compounds. In the presenceof an active ingredient, such as the included one or more cannabinoids,the tablet composition may preferably also comprise a carrier known inthe arts of tablet composition and active ingredients. Poloxamer F68 isa further highly suitable solubilizer.

High intensity artificial sweetening agents can also be used accordingto preferred embodiments of the invention. Preferred high intensitysweeteners include, but are not limited to sucralose, aspartame, saltsof acesulfame, alitame, neotame, saccharin and its salts, cyclamic acidand its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, monkfruit extract, advantame, stevioside and the like, alone or incombination.

In order to provide longer lasting sweetness and flavor perception, itmay be desirable to encapsulate or otherwise control the release of atleast a portion of the artificial sweeteners.

Techniques such as wet granulation, wax granulation, spray drying, spraychilling, fluid bed coating, conservation, encapsulation in yeast cellsand fiber extrusion may be used to achieve desired releasecharacteristics. Encapsulation of sweetening agents can also be providedusing another tablet composition component such as a resinous compound.

Usage level of the high-intensity sweetener will vary considerably andwill depend on factors such as potency of the sweetener, rate ofrelease, desired sweetness of the product, level and type of flavor usedand cost considerations. Thus, the active level of artificial sweetenermay vary from about 0.001 to about 8% by weight (preferably from about0.02 to about 8% by weight). When carriers used for encapsulation areincluded, the usage level of the encapsulated high-intensity sweetenerwill be proportionately higher.

A tablet composition and/or lozenge composition may, if desired, includeone or more fillers/texturizers including as examples, magnesium- andcalcium carbonate, sodium sulphate, ground limestone, silicate compoundssuch as magnesium- and aluminum silicate, kaolin and clay, aluminumoxide, silicium oxide, talc, titanium oxide, mono-, di- and tri-calciumphosphates, cellulose polymers, such as wood, and combinations thereof.According to an embodiment of the invention, one preferredfiller/texturizer is calcium carbonate.

A number of tablet composition components well known within the art maybe applied within the scope of the present invention. Such componentscomprise but are not limited to waxes, fats, softeners, fillers, bulksweeteners, flavors, antioxidants, emulsifiers, coloring agents, bindingagents and acidulants.

In an embodiment of the invention, water-soluble ingredients comprise atleast one sugar alcohol. The at least one sugar alcohol may be selectedfrom the group consisting of xylitol, sorbitol, mannitol, maltitol,isomaltitol, isomalt, erythritol, lactitol, maltodextrin, hydrogenatedstarch hydrolysates, and combinations thereof.

In an aspect of the invention, the sugar alcohol of the invention may bereplaced by one or more sugars, such as a sugar selected from the groupconsisting of dextrose, sucrose, maltose, fructose, lactose, andcombinations thereof.

Sugar sweeteners generally include, but are not limited tosaccharide-containing components, such as sucrose, dextrose, maltose,saccharose, lactose, sorbose, dextrin, trehalose, D-tagatose, driedinvert sugar, fructose, levulose, galactose, corn syrup solids, glucosesyrup, hydrogenated glucose syrup, and the like, alone or incombination. These sugar sweeteners may also be included as a humectant.

The tablet according to the invention is manufactured by applyingpressure to a content of particles by suitable compression means. Theparticles or powder is then pressed into a compact coherent tablet. Theparticles may for example comprise so-called primary particles oraggregated primary particles. When these are pressed, bonds areestablished between the particles or granules, thereby conferring acertain mechanical strength to the pressed tablet.

It should be noted that the above-introduced terms: powder, primaryparticles and aggregated primary particles may be somewhat misleading inthe sense that the difference between primary particles and aggregatedprimary particles may very often be looked upon differently depending onthe background of the user. Some may for instance regard a sweetener,such as sorbitol, as a primary particle in spite of the fact thatsorbitol due to the typically preprocessing performed on sorbitol whendelivered to the customer should rather be regarded as some sort ofaggregated primary particles. The definition adopted in the descriptionof this invention is that aggregated primary particles refer tomacro-particles comprising more or less preprocessed primary particles.

When pressure is applied to the particles, the bulk volume is reduced,and the amount of air is decreased. During this process energy isconsumed. As the particles come into closer proximity to each otherduring the volume reduction process, bonds may be established betweenthe particles or granules. The formation of bonds is associated with areduction in the energy of the system as energy is released. Volumereduction takes place by various mechanisms and different types of bondsmay be established between the particles or granules depending on thepressure applied and the properties of the particles or granules. Thefirst thing that happens when a powder is pressed is that the particlesare rearranged under low compaction pressures to form a closer packingstructure. Particles with a regular shape appear to undergorearrangement more easily than those of irregular shape. As the pressureincreases, further rearrangement is prevented, and subsequent volumereduction is obtained by plastic and elastic deformation and/orfragmentation of the tablet particles. Brittle particles are likely toundergo fragmentation, i.e. breakage of the original particles intosmaller units. Plastic deformation is an irreversible process resultingin a permanent change of particle shape, whereas the particles resumetheir original shape after elastic deformation. Evidently, both plasticand elastic deformation may occur, when compressing a tabletcomposition.

By the method of the invention, it is possible to form one-layered ormulti-layered tablets, such as two-layered tablets or three-layeredtablets.

Several studies of the bond types in pressed tablets have been made overthe years, typically in the context of pharmaceuticals and severaltechniques of obtaining pressed tablets on the basis of availablepowders has been provided. Such studies have been quite focused on whathappens when the volume reduction is performed and how the end-productmay be optimized for the given purpose. Several refinements with respectto pressed tablets has for instance been made in the addition of forexample binders in the tablet raw materials for the purpose of obtaininga sufficient strength to the final pressed tablet while maintainingacceptable properties, e.g. with respect to release.

In accordance with the invention, the tableted tablet compositionaccording to the invention may comprise about 0.1 to about 75% by weightof an outer coating applied onto the tablet composition centre. Thus,suitable coating types include hard coatings, film coatings and softcoatings of any composition including those currently used in coating oftableted tablet composition.

One presently preferred outer coating type is a hard coating, which termis used in the conventional meaning of that term including sugarcoatings and sugar-free (or sugarless) coatings and combinationsthereof. The object of hard coating is to obtain a sweet, crunchy layer,which is appreciated by the consumer and it may moreover protect thetablet composition centres for various reasons. In a typical process ofproviding the tablet composition centres with a protective sugarcoating, the tablet composition centres are successively treated insuitable coating equipment with aqueous solutions of crystallisablesugar such as sucrose or dextrose, which, depending on the stage ofcoating reached, may contain other functional ingredients, e.g. fillers,binding agents, colours, etc. In the present context, the sugar coatingmay contain further functional or active compounds including flavourcompounds and/or active compounds.

In a typical hard coating process as it will be described in detail inthe following, a suspension containing crystallisable sugar and/orpolyol is applied onto the tablet composition centres and the water itcontains is evaporated off by blowing with air. This cycle must berepeated several times, typically 3 to 80 times, in order to reach theswelling required. The term “swelling” refers to the increase in weightor thickness of the products, as considered at the end of the coatingoperation by comparison with the beginning, and in relation to the finalweight or thickness of the coated products. In accordance with thepresent invention, the coating layer constitutes about 0.1 to about 75%by weight of the finished tablet composition element, such as about 10to about 60% by weight, including about 15 to about 50% by weight.

In further useful embodiments, the outer coating of the tabletcomposition element of the invention is an element that is subjected toa film coating process and which therefore comprises one or morefilm-forming polymeric agents and optionally one or more auxiliarycompounds, e.g. plasticizers, pigments and opacifiers. A film coating isa thin polymer-based coating applied to a tablet composition centre ofany of the above forms. The thickness of such a coating is usuallybetween 20 and 100 μm.

Generally, the film coating is obtained by passing the tabletcomposition centres through a spray zone with atomized droplets of thecoating materials in a suitable aqueous or organic solvent vehicle,after which the material adhering to the tablet composition centres isdried before the next portion of coating is received. This cycle isrepeated until the coating is complete.

In the present context, suitable film-coating polymers include ediblecellulose derivatives such as cellulose ethers including methylcellulose(MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) andhydroxypropyl methylcellulose (HPMC). Other useful film-coating agentsare acrylic polymers and copolymers, e.g. methylacrylate aminoestercopolymer or mixtures of cellulose derivatives and acrylic polymers. Aparticular group of film-coating polymers, also referred to asfunctional polymers are polymers that, in addition to its film-formingcharacteristics, confer a modified release performance with respect toactive components of the tablet composition formulation. Such releasemodifying polymers include methylacrylate ester copolymers,ethylcellulose (EC) and enteric polymers designed to resist the acidicstomach environment. The latter group of polymers include: celluloseacetate phtalate (CAP), polyvinyl acetate phtalate (PVAP), shellac,metacrylic acid copolymers, cellulose acetate trimellitate (CAT) andHPMC. It will be appreciated that the outer film coating according tothe present invention may comprise any combination of the abovefilm-coating polymers.

According to the invention, the one or more cannabinoids may be selectedfrom various cannabinoids.

“Cannabinoids” are a group of compounds including the endocannabinoids,the phytocannabinoids and those which are neither endocannabinoids orphytocannabinoids, hereinafter “syntho-cannabinoids”.

“Endocannabinoids” are endogenous cannabinoids, which may have highaffinity ligands of CB1 and CB2 receptors.

“Phytocannabinoids” are cannabinoids that originate in nature and can befound in the cannabis plant. The phytocannabinoids can be present in anextract including a botanical drug substance, isolated, or reproducedsynthetically.

“Syntho-cannabinoids” are those compounds capable of interacting withthe cannabinoid receptors (CB1 and/or CB2) but are not foundendogenously or in the cannabis plant. Examples include WIN 55212 andrimonabant.

An “isolated phytocannabinoid” is one which has been extracted from thecannabis plant and purified to such an extent that the additionalcomponents such as secondary and minor cannabinoids and thenon-cannabinoid fraction have been substantially removed.

A “synthetic cannabinoid” is one which has been produced by chemicalsynthesis. This term includes modifying an isolated phytocannabinoid,by, for example, forming a pharmaceutically acceptable salt thereof.

A “substantially pure” cannabinoid is defined as a cannabinoid which ispresent at greater than 95% (w/w) pure. More preferably greater than 96%(w/w) through 97% (w/w) thorough 98% (w/w) to 99% % (w/w) and greater.

A “highly purified” cannabinoid is defined as a cannabinoid that hasbeen extracted from the cannabis plant and purified to the extent thatother cannabinoids and non-cannabinoid components that are co-extractedwith the cannabinoids have been substantially removed, such that thehighly purified cannabinoid is greater than or equal to 95% (w/w) pure.

“Plant material” is defined as a plant or plant part (e.g. bark, wood,leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof)as well as exudates, and includes material falling within the definitionof “botanical raw material” in the Guidance for Industry Botanical DrugProducts Draft Guidance, August 2000, US Department of Health and HumanServices, Food and Drug Administration Center for Drug Evaluation andResearch.

In the context of this application the terms “cannabinoid extract” or“extract of cannabinoids”, which are used interchangeably, encompass“Botanical Drug Substances” derived from cannabis plant material. ABotanical Drug Substance is defined in the Guidance for IndustryBotanical Drug Products Draft Guidance, August 2000, US Department ofHealth and Human Services, Food and Drug Administration Centre for DrugEvaluation and Research as: “A drug substance derived from one or moreplants, algae, or macroscopic fungi. It is prepared from botanical rawmaterials by one or more of the following processes:

pulverisation, decoction, expression, aqueous extraction, ethanolicextraction, or other similar processes.” A botanical drug substance doesnot include a highly purified or chemically modified substance derivedfrom natural sources. Thus, in the case of cannabis, “botanical drugsubstances” derived from cannabis plants do not include highly purified,Pharmacopoeial grade cannabinoids.

The term “Cannabis plant(s)” encompasses wild type Cannabis sativa andalso variants thereof, including cannabis chemovars which naturallycontain different amounts of the individual cannabinoids, Cannabissativa subspecies indica including the variants var. indica and var.kafiristanica, Cannabis indica, Cannabis ruderalis and also plants whichare the result of genetic crosses, self-crosses or hybrids thereof. Theterm “Cannabis plant material” is to be interpreted accordingly asencompassing plant material derived from one or more cannabis plants.For the avoidance of doubt it is hereby stated that “cannabis plantmaterial” includes dried cannabis biomass.

Preferably the one or more cannabinoids are selected from:cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol(CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO),tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA). More preferably the one or more cannabinoid is CBD or THC. This listis not exhaustive and merely details the cannabinoids which areidentified in the present application for reference.

So far, more than 120 different phytocannabinoids have been identifiedwhich are within the scope of the present invention.

Cannabinoids can be split into different groups as follows:Phytocannabinoids; Endocannabinoids; and Synthetic cannabinoids.

Cannabinoid receptors can be activated by three major groups of agonistligands, for the purposes of the present invention and whether or notexplicitly denominated as such herein, lipophilic in nature and classedrespectively as: endocannabinoids (produced endogenously by mammaliancells); phytocannabinoids (such as cannabidiol, produced by the cannabisplant); and, synthetic cannabinoids (such as HU-210).

Phytocannabinoids can be found as either the neutral carboxylic acidform or the decarboxylated form depending on the method used to extractthe cannabinoids. For example, it is known that heating the carboxylicacid form will cause most of the carboxylic acid form to decarboxylate.

Phytocannabinoids can also occur as either the pentyl (5 carbon atoms)or propyl (3 carbon atoms) variant. For example, the phytocannabinoidTHC is known to be a CB1 receptor agonist whereas the propyl variantTHCV has been discovered to be a CB1 receptor antagonist meaning that ithas almost opposite effects.

According to the invention, examples of phytocannabinoids may becannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol(CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO),tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA). More preferably the one or more cannabinoid is CBD or THC.

The formulation according to the present invention may also comprise atleast one cannabinoid selected from those disclosed in A. DouglasKinghorn et al., Phytocannabinoids, Vol. 103, Chapter 1, pages 1-30.

Examples of endocannabinoids are molecules that activate the cannabinoidreceptors within the body. Examples include 2-arachidonyl glycerol(2AG), 2-arachidonyl glyceryl ether (2AGE), arachidonyl dopamine, andarachidonyl ethanolamide (anandamide). Structurally related endogenousmolecules have been identified that share similar structural features,but that display weak or no activity towards the cannabinoid receptorsbut are also termed endocannabinoids. Examples of these endocannabinoidlipids include 2-acyl glycerols, alkyl or alkenyl glyceryl ethers, acyldopamines and N-acylethanolamides that contain alternative fatty acid oralcohol moieties, as well as other fatty acid amides containingdifferent head groups. These include N-acylserines as well as many otherN-acylated amino acids. Examples of cannabinoid receptor agonists areneuromodulatory and affect short-term memory, appetite, stress response,anxiety, immune function and analgesia.

In one embodiment the cannabinoid is palmitoylethanolamide (PEA) whichis an endogenous fatty acid amide belonging to the class of nuclearfactor agonists.

Synthetic cannabinoids encompass a variety of distinct chemical classes:the cannabinoids structurally related to THC, the cannabinoids notrelated to THC, such as (cannabimimetics) including theaminoalkylindoles, 1,5-diarylpyrazoles, quinolines, andarylsulfonamides, and eicosanoids related to the endocannabinoids. Allor any of these cannabinoids can be used in the present invention.

It is preferred that the formulation comprises one or two primarycannabinoids, which are preferably selected from the group consistingof, cannabidiol (CBD) or cannabidivarin (CBDV), tetrahydrocannabinol(THC), tetrahydrocannabivarin (THCV), tetrahydrocannabinolic acid(THCA), cannabigerol (CBG) and cannabidiolic acid (CBDA) or acombination thereof. It is preferred that the formulation comprisescannabidiol and/or tetrahydrocannabinol.

Preferably, the tablet composition of the present invention may be usedfor the treatment or alleviation of pain, epilepsy, cancer, nausea,inflammation, congenital disorders, neurological disorders, oralinfections, dental pain, sleep apnea, psychiatric disorders,gastrointestinal disorders, inflammatory bowel disease, appetite loss,diabetes and fibromyalgia.

In a further aspect of the present invention the oral cannabinoidformulation is suitable for use in the treatment of conditions requiringthe administration of a neuroprotectant or anti-convulsive medication.

The oral cannabinoid formulation may be for use in the treatment ofseizures.

The oral cannabinoid formulation may be for use in the treatment ofDravet syndrome, Lennox Gastaut syndrome, myoclonic seizures, juvenilemyoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms,West syndrome, infantile spasms, refractory infantile spasms, tuberoussclerosis complex, brain tumours, neuropathic pain, cannabis usedisorder, post-traumatic stress disorder, anxiety, early psychosis,Alzheimer's disease, and autism.

The following non-limiting examples illustrate different variations ofthe present invention. The examples are meant for indicating theinventive concept; hence the mentioned examples should not be understoodas exhaustive for the present. In particular, CBD is used as anexemplary compound, but may also be another cannabinoid.

EXAMPLES Example 1 Component with CBD Extract 50%

CBD extract with a 50% content of CBD provided by CBDepot (batch numberCSFF 2018/5) was preheated to around 60° C. for around 0.5 to 1 houruntil the extract was in liquid form. The extract had, besidecannabinoids, a content of fatty acids, glycerol, waxes, terpenes andflavonoids. After the preheating process, the extract was applied as athin layer on top of one or more sugar alcohol particles. After mixinguntil CBD was homogeneously distributed in the one or more sugar alcoholparticles, the mixture was sieved through a 1400 microns sieve.

Example 2 Component with CBD Extract 10%

CBD extract with a 10% content of CBD provided by Medical Hemp (batchnumber MH131B Gold), was preheated to around 60° C. for around 0.5 to 1hour until the extract was in liquid form. The extract had, besidecannabinoids, a content of fatty acids, glycerol, waxes, terpenes andflavonoids. After the preheating process, the extract was applied as athin layer on top of one or more sugar alcohol particles. After mixinguntil CBD was homogeneously distributed in the one or more sugar alcoholparticles, the mixture was sieved through a 1400 microns sieve.

Example 3 Component with CBD Isolate with a Solvent

CBD isolate from cannabis plant tissues (phytocannabinoid) with a 98.5%content of CBD provided by Medical Hemp (batch number MH18212) wasdissolved in a 96% ethanol solution. The ratio between the CBD isolateand ethanol was 1:1. Once CBD was dissolved in ethanol, the CBD isolatewas applied in a premix with one or more sugar alcohol particles. Aftermixing until CBD was homogeneously distributed in the one or more sugaralcohol particles, the mixture was sieved through a 1400 microns sieve.

Example 4 Component with CBD Isolate without a Solvent

CBD isolate from cannabis plant tissues (phytocannabinoid) with a 98.5%content of CBD provided by Medical Hemp (batch number MH18212) was addedas free powder and mixed with one or more sugar alcohol particles.

After mixing until CBD was homogeneously distributed in the one or moresugar alcohol particles, the mixture was sieved through a 1400 micronssieve.

Example 5 Component Including Microcrystalline Cellulose

CBD extract with a 50% content of CBD provided by CBDepot (batch numberCSFF 2018/5) was preheated to around 60° C. for around 0.5 to 1 houruntil the extract was in liquid form. The extract had, besidecannabinoids, a content of fatty acids, glycerol, waxes, terpenes andflavonoids. After the preheating process, the extract was applied as athin layer on microcrystalline cellulose (MCC). Mixing was conducteduntil the CBD was homogeneously distributed in the MCC. Optionally, theCBD-MCC premix could be further mixed with one or more sugar alcoholparticles. The mixture was sieved through a 1400 microns sieve.

Example 6 Component Including Silicium Dioxide Carrier

CBD extract with a 50% content of CBD provided by CBDepot (batch numberCSFF 2018/5) was preheated to around 60° C. for around 0.5 to 1 houruntil the extract was in liquid form. The extract had, besidecannabinoids, a content of fatty acids, glycerol, waxes, terpenes andflavonoids. After the preheating process, the extract was applied as athin layer on silicium dioxide (SiO2). Mixing was conducted until theCBD was homogeneously distributed in the SiO2. Optionally, the CBD-SiO2premix could be further mixed with one or more sugar alcohol particles.The mixture was sieved through a 1400 microns sieve.

Example 7 Component Including Hyperporous SilicaMagnesium-Alumino-Metasilicates

CBD extract with a 50% content of CBD provided by CBDepot (batch numberCSFF 2018/5) was preheated to around 60° C. for around 0.5 to 1 houruntil the extract was in liquid form. The extract had, besidecannabinoids, a content of fatty acids, glycerol, waxes, terpenes andflavonoids. After the preheating process, the extract was applied as athin layer on hyperporous silica magnesium-alumino-metasilicates. Mixingwas conducted until the CBD was homogeneously distributed in thehyperporous silica magnesium-alumino-metasilicates. Optionally, theCBD-hyperporous silica magnesium-alumino-metasilicates premix could befurther mixed with one or more sugar alcohol particles. The mixture wassieved through a 1400 microns sieve.

Example 8 Preparation of Cannabinoid Component with Emulsifier and Oil

Solution of Labrafil M 1944 CS and Maisine CC (1:1) was mixed. CBDisolate from Example 3 or CBD extract from Example 1 was added anddissolved in the solution to obtain a 33% solution of CBD, using aVortex mixer. The solution with CBD was applied in a premix with one ormore sugar alcohols. After mixing until CBD was homogeneouslydistributed in the one or more sugar alcohols, the mixture was sievedthrough a 1400 microns sieve.

Example 9 Preparation of Cannabinoid Component with Emulsifier, Oil andCo-Solvent

Solution of 60% Labrafac Lipophile WL1349 and 25% Labrasol and 15%Propylene Glycol was mixed. CBD isolate from Example 3 or CBD extractfrom Example 1 was added and dissolved in the solution to obtain a 33%solution of CBD, using a Vortex mixer. The solution with CBD was appliedin a premix with one or more sugar alcohols. After mixing until CBD washomogeneously distributed in the one or more sugar alcohols, the mixturewas sieved through a 1400 microns sieve.

Example 10 Preparation of Cannabinoid Component with Solid Solubilizer

Gelucire 50/13 was melted at app. 60° C. and CBD isolate from Example 3or CBD extract from Example 1 was added and dissolved in the meltedsolution to obtain a 50% solution of CBD, using a Vortex mixer. Thesolution with CBD was applied in a premix with one or more sugaralcohols. After mixing until CBD was homogeneously distributed in theone or more sugar alcohols, the mixture was sieved through a 1400microns sieve.

Example 11 Preparation of Cannabinoid Component with Emulsifier andCo-Solvent

CBD extract from Example 1 was preheated at 60° C., until it was inliquid form and then dissolved in Propylene Glycol. Labrasol ALF wasthen added to obtain a 17% solution of CBD, using a Vortex mixer. Thesolution with CBD was applied in a premix with one or more sugaralcohols. After mixing until CBD was homogeneously distributed in theone or more sugar alcohols, the mixture was sieved through a 1400microns sieve.

Example 12 Preparation of Cannabinoid Component with an AmphiphilicPolymer Carrier

CBD extract from Example 1 was preheated at 60° C. until it was inliquid form. After the preheating process, the extract was applied in apremix with Soluplus (graft-co-polymer provided by BASF) and mixed untilthe premix was homogeneous, obtaining a 12.5% premix of CBD. The premixwas then mixed with one or more sugar alcohols. After mixing until CBDwas homogeneously distributed in the one or more sugar alcohols, themixture was sieved through a 1400 microns sieve.

Example 13 Preparation of Cannabinoid Component with Cyclodextrin andEmulsifier

CBD isolate from Example 3 was added and dissolved in polysorbate 80 toobtain a 10% solution of CBD. The 10% CBD solution was slowly added andmixed into a solution with 4% cyclodextrin to form a CBD-cyclodextrincomplex. The water was removed, whereupon the complex was applied in apremix with one or more sugar alcohols. After mixing until theCBD-cyclodextrin complex was homogeneously distributed in the one ormore sugar alcohols, the mixture was sieved through a 1400 micronssieve.

Example 14 A: Preparation of Fast Disintegrating Tablet (FDT) with OneLayer

A cannabinoid component from either one of Examples 1 to 13 and FDTcomponents were blended in a mixing container at about 7-9 rpm andoptionally loaded with processing aid in order to improve free-flowingproperties of the particles and to avoid stickiness.

In a first step, half the FDT components were added to a mixingcontainer. High-intensity sweetener (HIS), flavors and the cannabinoidcomponent were added to the container, after which the other half of theFDT components were added. Optionally, a premix of cannabinoids wasapplied. The mixture was tumbled at 7-9 rpm for 10 minutes. A processingaid was added and the mixture was tumbled at 7-9 rpm for another 2minute. Hereafter, the mixture was ready for tableting.

FDT components include sugar alcohol particles, such as mannitolparticles. Mannitol applied according to the examples was mannitol 200SD commercially available from Roquette with different average particlesizes. Isomalt particles applied according to the examples was GalenlQ720 commercially available from Beneo. Microcrystalline celluloseapplied according to the examples was Avicel PH-105 commerciallyavailable from FMC. FDT components also include one or moredisintegrants. Here crospovidone was applied in a grade available asKollidon CL-SF available from BASF).

The mixture was subsequently led to a standard tablet pressing machine(3090i, available from Fette GmbH) comprising dosing apparatus (P 3200C, available from Fette GmbH, Germany) and pressed into FDT tablets. Thetablets were pressed using a pressing pressure of 15-20 kN. There were75 punches on the rotor, and the rotor speed used was 11 rpm. Theindividual tablets had a weight of approx. 150 mg. The content of CBD inthe FDT tablets was 10 mg, unless otherwise stated. Punch used: 10.00mm, circular, shallow concave, D tooling.

B: Preparation of Tablet with Two Layers

A layer prepared in the same way as in Example 14A was tableted as thefirst layer after which the layer of Example 14A (here denoted thesecond layer) was tableted on top of this first made layer. The ratio ofthe ingredients was different in this first layer. The weight ratio ofthe two layers was 70 to 30 (first layer to second layer). Here layer 1is a lozenge layer and layer 2 is an FDT layer. The individual tabletshad a weight of approx. 500 mg with layer 1 being 350 mg and layer 2being 150 mg. The content of CBD in the tablets was 10 mg in total,unless otherwise stated. Punch used: 10.00 mm, circular, shallowconcave, D tooling. Layer 1 is then compressed at a compression force ofabout 3 kN, after which layer 2 is fused by compression to layer 1 at acompression force of 20 kN. The tablet machine is commissioned byadjusting the fill depth and compression force so the weight andhardness of tablets match the acceptance criteria. A pre-compressionforce could be included to avoid capping.

Example 15 Composition of Cannabinoid Tablets with Different CBD Source

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 1 It was secured that CBD was thoroughly mixed into thepremixture. 100 101 102 103 104 Tablet Number Content Content ContentContent Content Raw material name [%] [%] [%] [%] [%] Pre-mixturecomponent Mannitol 30.0 30.0 30.0 30.0 30.0 CBD-extract (loaded 13.313.3 50%) CBD isolate (loaded 6.8 6.8* 6.8 98.5%)-dissolved in ethanol1:1 (Example 3) FDT components Mannitol 46.9 41.9 53.4 53.4 48.4 Flavor4.2 4.2 4.2 4.2 4.2 HIS 0.1 0.1 0.1 0.1 0.1 Processing aids 0.5 0.5 0.50.5 0.5 Crospovidone 5.0 10.0 5.0 5.0 10.0 Total 100 100 100 100 100*CBD isolate has been added loosely to the pre-mixture-not dissolved inethanol-according to the procedure in Example 4 (deviation of theprocedure in Example 3).

Example 16 Composition of Cannabinoid Tablets with Different Ratios ofPremixture

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 2 It was secured that CBD was thoroughly mixed into thepremixture. 105 106 107 108 Tablet Number Content Content ContentContent Raw material name [%] [%] [%] [%] Pre-mixture component Mannitol20.0 25.0 40.0 50.0 CBD-extract (loaded 50%) 13.3 13.3 13.3 13.3 FDTcomponents Mannitol 56.9 51.9 36.9 26.9 Flavor 4.2 4.2 4.2 4.2 HIS 0.10.1 0.1 0.1 Processing aids 0.5 0.5 0.5 0.5 Crospovidone 5.0 5.0 5.0 5.0Total 100 100 100 100

Example 17 Composition of Cannabinoid Tablets with Different SugarAlcohol Particles

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 3 It was secured that CBD was thoroughly mixed into thepremixture. 109 110 111 112 113 Tablet Number Content Content ContentContent Content Raw material name [%] [%] [%] [%] [%] Pre-mixturecomponent Isomalt 30 Xylitol 30 Mannitol 30 Maltitol 30 Sorbitol 30CBD-extract (loaded 50%) 13.3 13.3 13.3 13.3 13.3 FDT components Isomalt46.9 Xylitol 46.9 Mannitol 46.9 Maltitol 46.9 Sorbitol 46.9 Flavor 4.24.2 4.2 4.2 4.2 HIS 0.1 0.1 0.1 0.1 0.1 Processing aids 0.5 0.5 0.5 0.50.5 Crospovidone 5.0 5.0 5.0 5.0 5.0 Total 100 100 100 100 100

Example 18 Composition of Cannabinoid Tablets with DifferentDisintegrants

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 4 It was secured that CBD was thoroughly mixed into thepremixture. 114 115 116 117 118 119 Tablet Number Content ContentContent Content Content Content Raw material name [%] [%] [%] [%] [%][%] Pre-mixture component Mannitol 30.0 30.0 30.0 30.0 30.0 30.0CBD-extract (loaded 50%) 13.3 13.3 13.3 13.3 13.3 13.3 FDT componentsMannitol 46.9 46.9 46.9 26.9 26.9 26.9 Microcrystalline cellulose (MCC)20.0 20.0 20.0 Flavor 4.2 4.2 4.2 4.2 4.2 4.2 HIS 0.1 0.1 0.1 0.1 0.10.1 Processing aids 0.5 0.5 0.5 0.5 0.5 0.5 Crospovidone 5.0 5.0Croscarmellose Sodium 5.0 5.0 Sodium Starch Glycolate 5.0 5.0 Total 100100 100 100 100 100

Example 19 Composition of Cannabinoid Tablets with MicrocrystallineCellulose in Premix

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 5 It was secured that CBD was thoroughly mixed into thepremixture. 120 121 122 123 124 125 Tablet Number Content ContentContent Content Content Content Raw material name [%] [%] [%] [%] [%][%] Pre-mixture component Mannitol 30 30 30 30 30 30 Microcrystalline 36 15 6 6 cellulose (MCC) CBD-extract (loaded 50%) 13.3 13.3 13.3 13.3CBD isolate (loaded 98.5%)- 6.8* 6.8 dissolved in ethanol 1:1 (Ex 3) FDTcomponents Mannitol 46.9 43.9 40.9 31.9 47.4 47.4 Flavor 4.2 4.2 4.2 4.24.2 4.2 HIS 0.1 0.1 0.1 0.1 0.1 0.1 Processing aids 0.5 0.5 0.5 0.5 0.50.5 Crospovidone 5.0 5.0 5.0 5.0 5.0 5.0 Total 100 100 100 100 100 100*CBD isolate has been added loosely to the pre-mixture-not dissolved inethanol-according to the procedure in Example 4 (deviation of theprocedure in Example 3).

Example 20 Composition of Cannabinoid Tablets with Different Carriers

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 6 It was secured that CBD was thoroughly mixed into thepremixture. 126 127 128 129 130 131 Tablet Number Content ContentContent Content Content Content Raw material name [%] [%] [%] [%] [%][%] Pre-mixture component Mannitol 30 30 30 30 30 30 Hyperporouscarrier** 3 6 3 SiO2 3 6 3 CBD-extract (loaded 50%) 13.3 13.3 13.3 13.3CBD isolate (loaded 98.5%)- 6.8* 6.8* dissolved in ethanol 1:1 (Ex 3)FDT components Mannitol 43.9 40.9 43.9 40.9 50.4 50.4 Flavor 4.2 4.2 4.24.2 4.2 4.2 HIS 0.1 0.1 0.1 0.1 0.1 0.1 Processing aids 0.5 0.5 0.5 0.50.5 0.5 Crospovidone 5.0 5.0 5.0 5.0 5.0 5.0 Total 100 100 100 100 100100 *CBD isolate has been added loosely to the pre-mixture-not dissolvedin ethanol-according to the procedure in Example 4 (deviation of theprocedure in Example 3). Hyperporous carrier** hyperporous silicamagnesium-alumino-metasilicates.

Example 21 Composition of Cannabinoid Tablets with Different Levels ofDisintegrant

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 7 It was secured that CBD was thoroughly mixed into thepremixture. Tablet Number 132 Content 133 Content 134 Content 135Content 136 Content 137 Content Raw material name [%] [%] [%] [%] [%][%] Pre-mixture component Mannitol 30 30 30 30 30 30 CBD-extract (loaded50%) 13.3 13.3 13.3 13.3 13.3 13.3 FDT components Mannitol 49.9 47.945.9 43.9 41.9 36.9 Flavor 4.2 4.2 4.2 4.2 4.2 4.2 HIS 0.1 0.1 0.1 0.10.1 0.1 Processing aids 0.5 0.5 0.5 0.5 0.5 0.5 Crospovidone 2.0 4.0 6.08.0 10.0 15.0 Total 100 100 100 100 100 100 *CBD isolate has been addedloosely to the pre-mixture-not dissolved in ethanol-according to theprocedure in Example 4 (deviation of the procedure in Example 3).

Example 22 Composition of Cannabinoid Tablets with DifferentSelf-Emulsifying Drug Delivery System (SEDDS) Components

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 8 It was secured that CBD was thoroughly mixed into thepremixture. Tablet Number 138 Content 139 Content 140 Content 141Content 142 Content 143 Content Raw material name [%] [%] [%] [%] [%][%] Pre-mixture component Mannitol 30.0 30.0 30.0 20.0 10.0 10.0CBD-extract (loaded 50%) 13.3 13.3 CBD isolate (loaded 98.5%) 6.8 6.86.8 Labrafil M 1944 CS 6.8 Gelucire 50/13 6.8 Labrasol ALF 3.3 13.3Maisine CC 13.3 Labrafac 8.0 Lipophile WL 1349 Propylene Glycol 2.0 13.3Soluplus 40.0 CBD-cyclodextrin 40.0 FDT components Mannitol 33.3 30.146.6 30.3 26.9 40.2 Flavors 4.2 4.2 4.2 4.2 4.2 4.2 HIS 0.1 0.1 0.1 0.10.1 0.1 Processing aids 0.5 0.5 0.5 0.5 0.5 0.5 Crospovidone 5.0 5.0 5.05.0 5.0 5.0 Total 100 100 100 100 100 100

Example 23 Preparation of Fast Disintegrating Tablet

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In these example, thefollowing conditions where applied. Punch used: 7.00 mm, circular,shallow concave, B tooling. Tablet weight: 100.0 mg. In these examples,the amount of the various ingredients is given as mg.

TABLE 9 Fast disintegrating tablet compositions with CBD isolate.Amounts are given in mg. FDT(a) FDT(b) FDT(c) FDT(d) FDT(e) FDT(f) CBD10.0 10.0 10.0 10.0 10.0 10.0 Microcrystalline — — — 39.6 39.6 39.6cellulose Mannitol 79.2 79.2 79.2 39.6 39.6 39.6 Crospovidone 5.0 — —5.0 — — Croscarmellose — 5.0 — — 5.0 — Sodium Sodium Starch — — 5.0 — —5.0 Glycolate Peppermint 4.0 4.0 4.0 4.0 4.0 4.0 Menthol 0.4 0.4 0.4 0.40.4 0.4 Sucralose 0.4 0.4 0.4 0.4 0.4 0.4 Silicium dioxide — — — 1.0 1.01.0 Magnesium 1.0 1.0 1.0 1.0 1.0 1.0 stearate Total 100.0 100.0 100.0100.0 100.0 100.0 FDT = Fast disintegrating tablet.

Example 24 Composition of Cannabinoid Tablets with Ready to UseDisintegrants

Cannabinoid tablets based on the procedure in Example 14A were made withthe formulations outlined in the examples below. In these example, thefollowing conditions where applied. Punch used: 7.00 mm, circular,shallow concave, B tooling. Tablet weight: 100.0 mg. In these examples,the amount of the various ingredients is given as mg.

Another way of preparing fast disintegrating tablets would be to use aready to use system. In the present example five fast disintegratingtablets (FDT(g)-FDT(k)) without cannabinoids are prepared with ready touse systems in formulations as outlined in Table 10.

TABLE 10 Fast disintegrating tablet compositions with different ready touse systems. Amounts are given in mg. FDT(g) FDT(h) FDT(i) FDT(j) FDT(k)Ludiflash 86.7 — — — — Pearlitol Flash — 86.7 — — — SmartEx QD50 — —86.7 — — F-Melt — — — 88.7 — ProSolv ODT G2 — — — — 88.7 Peppermint 4.44.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.5 1.5 Sucralose 0.4 0.4 0.4 0.40.4 Crospovidone 5.0 5.0 5.0 — — Croscarmellose — — — 3.0 — SodiumSodium Starch — — — — 3.0 Glycolate Magnesium 2.0 2.0 2.0 2.0 2.0stearate Total 100.0 100.0 100.0 100.0 100.0 FDT = Fast disintegratingtablet.

Additionally, five fast disintegrating tablets (FDT(I)-FDT(p)) withcannabinoids are prepared with ready to use systems in formulations asoutlined in Table 11.

TABLE 11 Fast disintegrating tablet compositions with different ready touse systems and CBD isolate. Amounts are given in mg. FDT(l) FDT(m)FDT(n) FDT(o) FDT(p) CBD 10.0 10.0 10.0 10.0 10.0 Ludiflash 76.7 — — — —Pearlitol Flash — 76.7 — — — SmartEx QD50 — — 76.7 — — F-Melt — — — 76.7— ProSolv ODT G2 — — — — 76.7 Peppermint 4.4 4.4 4.4 4.4 4.4 Menthol 1.51.5 1.5 1.5 1.5 Sucralose 0.4 0.4 0.4 0.4 0.4 Crospovidone 5.0 5.0 5.0 —— Croscarmellose — — — 3.0 — Sodium Sodium Starch — — — — 3.0 GlycolateMagnesium 2.0 2.0 2.0 2.0 2.0 stearate Total 100.0 100.0 100.0 100.0100.0 FDT = Fast disintegrating tablet.

Further four fast disintegrating tablets (FDT(1)-FDT(4)) withcannabinoids are prepared with varying amounts of MCC (microcrystallinecellulose) as filler, as outlined in Table 12.

TABLE 12 Fast disintegrating tablet compositions with varying amounts ofMCC and CBD as isolate. Amounts are given in mg. FDT(1) FDT(2) FDT(3)FDT(4) CBD 10.0 10.0 10.0 10.0 Microcrystalline cellulose (MCC) 0.0 5.010.0 20.0 Mannitol 77.7 72.7 67.7 57.7 Crospovidone 5.0 5.0 5.0 5.0Peppermint 4.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.5 Sucralose 0.4 0.4 0.40.4 Magnesium stearate 1.0 1.0 1.0 1.0 Total 100.0 100.0 100.0 100.0 FDT= Fast disintegrating tablet.

Four fast disintegrating tablets, FDT(5)-FDT(8), with cannabinoids areprepared with varying amounts of disintegrant, as outlined in Table 13.

TABLE 13 Fast disintegrating tablet compositions with varying amount ofdisintegrant and CBD isolate. Amounts are given in mg. FDT(5) FDT(6)FDT(7) FDT(8) CBD 10.0 10.0 10.0 10.0 Mannitol 39.7 37.2 39.7 29.7Microcrystalline cellulose (MCC) 43 43 43 43 Crospovidone 0.0 2.5 5.010.0 Peppermint 4.4 4.4 4.4 4.4 Menthol 1.5 1.5 1.5 1.5 Sucralose 0.40.4 0.4 0.4 Magnesium stearate 1.0 1.0 1.0 1.0 Total 100.0 100.0 100.0100.0 FDT = Fast disintegrating tablet.

Three fast disintegrating tablets, FDT(9)-FDT(11), with cannabinoids areprepared with varying types of lubricants, as outlined in Table 14.

TABLE 14 Fast disintegrating tablet compositions with different types oflubricants and CBD isolate. Amounts are given in mg. FDT(9) FDT(10)FDT(11) CBD 10.0 10.0 10.0 Microcrystalline cellulose (MCC) 5.0 5.0 5.0Mannitol 76.6 75.6 75.6 Crospovidone 5.0 5.0 5.0 Eucamenthol Flavour 2.02.0 2.0 Sucralose 0.4 0.4 0.4 Magnesium stearate 1.0 — — Sodium stearylfumarate — 2.0 — Compritol HD5 — — 2.0 Total 100.0 100.0 100.0 FDT =Fast disintegrating tablet.

Three fast disintegrating tablets, FDT(12-FDT(14), with cannabinoids areprepared, as outlined in Table 15.

In this example, the following conditions where applied. Punch used:7.00 mm, circular, shallow concave, B tooling. Tablet weight: 75.0 mg.

TABLE 15 Fast disintegrating tablet compositions with CBD isolate.Amounts are given in mg. FDT(12) FDT(13) FDT(14) SmartEx QD 50 53.0 58.058.0 CBD 10.0 10.0 10.0 Sodium carbonate anhydrous 5.0 0.0 5.0Crospovidone 5.0 5.0 0.0 Peppermint Powder 0.4 0.4 0.4 Sucralose 0.4 0.40.4 Silicium dioxide (Aerosil 200) 0.2 0.2 0.2 Magnesium Stearate 1.01.0 1.0 Total 75.0 75.0 75.0 FDT = Fast disintegrating tablet. FDT(13)was made similar to FDT(12) but without buffer. FDT(14) was made similarto FDT(12) but without disintegrant.

FDT(12)-FDT(13) were pressed to a hardness of 15-20 N. FDT (14) waspressed to a hardness of 25-35 N.

Example 25 Disintegration of Tablets

The in vitro disintegration of the fast disintegrating tablets ofExamples 15-24 was carried out in accordance to European Pharmacopeia9.0, section 2.9.1, Disintegration of tablets and capsules. The resultsfor Example 23 are outlined in Table 16. A minimum and a maximum valuefor measured disintegration are given and this is more or less afunction of the hardness.

TABLE 16 In vitro disintegration, hardness, friability. Time is given inseconds. Mean in vitro Mean disintegration hardness Mean (sec) (N)friability (%) Min Max Min Max Min Max (sec) (sec) (N) (N) (%) (%)FDT(a) 21 24 14 63 0.0 0.3 FDT(b) 23 98 12 50 0.0 0.6 FDT(c) 29 177 1455 0.0 0.5 FDT(d) 15 177 19 62 0.0 0.0 FDT(e) 13 175 15 45 0.0 0.2FDT(f) 11 259 14 43 0.0 0.2

The above table should be interpreted as illustrated in the followingexample. When looking at e.g. FDT(a), the minimum mean disintegrationtime of 21 seconds correspond to a tablet pressed just hard enough toobtain a cohesive tablet having a minimum mean hardness of 14 N and afriability of 0.3%. Similarly, the maximum mean disintegration time of24 seconds correspond to another tablet pressed harder to have a maximummean hardness of 63 N. In this way, the tablet having a mean friabilityof 0.0% of FDT(a) corresponds to the tablet having a mean hardness of 63N. In other words, in table 4 FDT(a) refers to two different tabletspressed at two different pressures, the linking being indicated above.I.e. each line corresponds to two different tablets, one for Min valuesof disintegration time and hardness and the Max value for friability,and another for Max values of disintegration time and hardness and theMin value for friability.

The results for Example 24 are outlined in Table 17.

TABLE 17 In vitro disintegration, hardness, friability. Time is given inseconds. Mean in vitro disintegration Mean hardness Mean (sec) (N)friability (%) Min Max Min Max Min Max (sec) (sec) (N) (N) (%) (%)FDT(g) 120 210 17 22 N/A 0.5 FDT(h) 40 80 16 24 0.5 0.8 FDT(i) 10 46 1722 0.3 0.3 FDT(j) 42 150 17 22 0.7 1.0 FDT(k) 45 201 17 22 0.6 0.9

The above table should be interpreted as illustrated in the examplebelow Table 16.

It is seen that the in vitro disintegrating may vary a lot between thedisclosed fast disintegrating tablets.

In vitro tests were also repeated for some of the ready to use systemsin FDT(I)-FDT(p).

The in vitro disintegration is a fast method to determine the time andmechanism for tablet performance. More preferable or in combination thein vivo disintegration is measured. The in vivo disintegration time is avalue for the actual disintegration of the tablet under the tongue.Table 18 and 19 highlights the results for in vivo disintegration.

TABLE 18 In vivo disintegration. Time is given in seconds. Mean in vivodisintegration (sec) Min (sec) Max (sec) FDT(a) 34 52 FDT(b) 18 27FDT(c) 37 N/A FDT(d) 42 N/A FDT(e) 46 N/A

TABLE 19 In vivo disintegration. Time is given in seconds. Mean in vivodisintegration (sec) Min (sec) Max (sec) FDT(g) 19 40 FDT(h) 13 48FDT(i) 32 80 FDT(j) N/A 56 FDT(k) N/A 81

The above Tables 18 and 19 should be interpreted as illustrated in theexample below Table 16.

In vivo tests were also repeated for some of the ready to use systems inFDT(I)-FDT(p).

As recognized for the in vitro disintegration results above the speed ofin vivo disintegrating may be varied between the disclosed batches. Thedisintegration time should be complete within 60 seconds from the onsetof disintegration or preferable faster.

Example 26 Composition of Cannabinoid Tablets with Two Layers

Cannabinoid tablets based on the procedure in Example 14B were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet layer.

TABLE 20 It was secured that CBD was thoroughly mixed into thepremixture. Content [%] Content [%] Raw material name Layer 1-350 mgLayer 2-150 mg Pre-mixture component Mannitol 50.0 40.0 CBD-extract(loaded 50%) 4.0 4.0 FDT components Mannitol 40.7 49.2 Flavor 4.2 4.2HIS 0.1 0.1 Processing aids 1.0 1.0 Crospovidone 1.5 Total 100 100

Example 27 Composition of Cannabinoid Two-Layered Tablets with DifferentLevels of CBD

Cannabinoid tablets based on the procedure in Example 14B were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet layer.

TABLE 21 Compositions of first and second layers. Tablet no. 1 2 3 4 5 67 8 Raw material layer 1 Content in weight percent of Layer 1 Mannitol98.25 98.25 98.25 98.25 98.25 98.25 98.25 98.25 Flavor 1 1 1 1 1 1 1 1HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.50.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Raw material layer2 Content in weight percent of Layer 2 Mannitol 84.25 80.25 76.95 75.2570.25 65.25 60.25 55.25 Disintegrant 8 8 8 8 8 8 8 8 Flavor 1 1 1 1 1 11 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 CBD-extract 6.0 10.013.3 15.0 20.0 25.0 30.0 35.0 (loaded 50%) MgSt 0.5 0.5 0.5 0.5 0.5 0.50.5 0.5 Total layer 2 100 100 100 100 100 100 100 100

Example 28 Composition of Cannabinoid Two-Layered Tablets with DifferentLevel of Super Disintegrant

Cannabinoid tablets based on the procedure in Example 14B were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet layer.

TABLE 22 Compositions of first and second layers. Super disintegrant isCrospovidone. Tablet no. 9 10 11 12 13 14 15 16 Raw material Content inweight percent of Layer 1 Mannitol 98.25 98.25 98.25 98.25 98.25 98.2598.25 98.25 Flavor 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.250.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Totallayer 1 100 100 100 100 100 100 100 100 Raw material Content in weightpercent of Layer 2 Mannitol 83.95 82.95 80.95 78.95 76.95 74.95 72.9570.95 Super 1 2 4 6 8 10 12 14 disintegrant Flavor 1.0 1.0 1.0 1.0 1.01.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 CBD-extract 13.313.3 13.3 13.3 13.3 13.3 13.3 13.3 (loaded 50%) MgSt 0.5 0.5 0.5 0.5 0.50.5 0.5 0.5 Total layer 2 100 100 100 100 100 100 100 100

Example 29 Composition of Cannabinoid Two-Layered Tablets with Ready toUse Disintegrant

Cannabinoid tablets based on the procedure in Example 14B were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet layer.

TABLE 23 Compositions of first and second layers. Content of starchdisintegrant is based on the content of starch in Pearlitol Flash.Tablet no. 17 18 19 20 21 22 23 24 Raw material Content in weightpercent of Layer 1 Mannitol 98.25 98.25 98.25 98.25 98.25 98.25 98.2598.25 Flavor 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.250.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1100 100 100 100 100 100 100 100 Raw material Content in weight percentof Layer 2 Content of starch 2 4 6 8 10 12 14 16 disintegrant Mannitol72.15 60.45 48.65 36.85 25.15 13.35 6.55 4.85 Pearlitol Flash 11.8 23.535.3 47.1 58.8 70.6 77.4 80.1 Flavor 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 HIS0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 CBD-extract 13.3 13.3 13.3 13.313.3 13.3 13.3 13.3 (loaded 50%) MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5Total layer 2 100 100 100 100 100 100 100 100

Example 30 Composition of Cannabinoid Two-Layered Tablets with CBD inBoth Layers

Cannabinoid tablets based on the procedure in Example 14B were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet layer.

TABLE 24 Compositions of first and second layers. Tablet no. 25 26 27 2829 30 31 32 Raw material Content in weight percent of Layer 1 Mannitol95.25 92.55 86.85 75.45 98.25 98.25 98.25 98.25 Flavor 1.0 1.0 1.0 1.01.0 1.0 1.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 CBD-extract3.0 5.7 11.4 22.8 — — — — (loaded 50%) MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.50.5 Total layer 1 100 100 100 100 100 100 100 100 Raw material Contentin weight percent of Layer 2 Mannitol 76.95 76.95 76.95 76.95 76.9576.95 76.95 76.95 Super disintegrant 8 8 8 8 8 8 8 8 Flavor 1 1 1 1 1 11 1 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 CBD-extract 13.3 13.313.3 13.3 13.3 13.3 13.3 13.3 (loaded 50%) MgSt 0.5 0.5 0.5 0.5 0.5 0.50.5 0.5 Total layer 2 100 100 100 100 100 100 100 100

Example 31A Composition of Cannabinoid Two-Layered Tablets withDifferent Sugar Alcohols

Cannabinoid tablets based on the procedure in Example 14B were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet layer.

TABLE 26 Compositions of first and second layers. Tablet no. 33 34 35 3637 38 39 40 Raw material Content in weight percent of Layer 1 Mannitol97.75 — — — 50.00 50.00 50.00 — Isomalt — 97.75 — — 47.75 — — 50.00Sorbitol — — 97.75 — — 47.75 — 47.75 Maltitol — — — 97.75 — — 47.75 —Buffer 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Flavor 1.0 1.0 1.0 1.0 1.0 1.01.0 1.0 HIS 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.50.5 0.5 0.5 0.5 Total layer 1 100 100 100 100 100 100 100 100 Rawmaterial Content in weight percent of Layer 2 Mannitol 76.95 67.15 56.9546.95 37.05 26.95 — 46.95 Erythritol — 10 20 30 40 50 76.95 — Xylitol —— — — — — — 30 Disintegrant 8 8 8 8 8 8 8 8 Flavor 1 1 1 1 1 1 1 1 HIS0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 CBD-extract 13.3 13.3 13.3 13.313.3 13.3 13.3 13.3 (loaded 50%) MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5Total layer 2 100 100 100 100 100 100 100 100

Example 31B Composition of Cannabinoid Two-Layered Tablets withDifferent Sugar Alcohols

Cannabinoid tablets based on the procedure in Example 14B were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet layer. Tablet no. 41-42 are 400 mg tablets each made with300 mg first layer and 100 mg second layer. Tablet no. 43-48 are 500 mgtablets each made with 350 mg first layer and 150 mg second layer.

TABLE 26 Compositions of first and second layers. Tablet no. 41 42 43 4445 46 47 48 Raw material Content in weight percent of Layer 1 Mannitol93.3 — — — — — — — Isomalt — 93.3 98.20 98.20 98.20 98.20 — 96.06Sorbitol — — — — — — 98.20 0 HIS 1.7 1.7 0.25 0.25 0.25 0.25 0.25 0.25Flavor 4.0 4.0 1.05 1.05 1.05 1.05 1.05 1.05 Xanthan gum — — — — — — —2.14 MgSt 1.0 1.0 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1 100 100 100 100100 100 100 100 Raw material Content in weight percent of Layer 2Mannitol 64.70 64.70 84.95 36.12 — 35.78 84.95 84.95 Erythritol — — — —— 49.07 — — Pearlitol Flash — — — 48.83 84.95 — — — Microcrystalline5.00 5.00 — — — — — — cellulose (MCC) Super 10.00 10.00 — — — — — —disintegrant Buffer 5.00 5.00 — — — — — — HIS — — 0.25 0.25 0.25 0.250.25 0.25 Flavor — — 1.00 1.00 1.00 1.00 1.00 1.00 MgSt — — 0.50 0.500.50 0.60 0.50 0.50 Sodium Stearyl 2.00 2.00 — — — — — — FumerateCBD-extract 13.3 13.3 13.3 13.3 13.3 13.3 13.3 13.3 (loaded 50%) Totallayer 2 100 100 100 100 100 100 100 100

Example 31C Composition of Cannabinoid Two-Layered Tablets withDifferent Cannabinoid Sources

Cannabinoid tablets based on the procedure in Example 14B were made withthe formulations outlined in the examples below. In all of the tabletexamples, the amount of the various ingredients is given as % by weightof the tablet.

TABLE 27 Compositions of first and second layers. Tablet no. 49 50 51 5253 54 55 56 Raw material layer 1 Content in weight percent of Layer 1Mannitol 97.75 97.75 97.75 97.75 97.75 97.75 97.75 97.75 Buffer 0.5 0.50.5 0.5 0.5 0.5 0.5 0.5 Flavor 1 1 1 1 1 1 1 1 HIS 0.25 0.25 0.25 0.250.25 0.25 0.25 0.25 MgSt 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Total layer 1100 100 100 100 100 100 100 100 Raw material layer 2 Content in weightpercent of Layer 2 CBD isolate 20.4 — — — — — — — (loaded 98.5%)-dissolved in ethanol 1:1 (Example 3)- MCC* CBD-extract — 39.9 — — — — —— (loaded 50%)- MCC* CBD isolate 20.4 (loaded 98.5%)- dissolved inethanol 1:1 (Example 3)- sugar alcohol* CBD-extract — — — 39.9 — — — —(loaded 50%)- sugar alcohol* CBD-extract — — — — 13.3 13.3 13.3 13.3(loaded 50%) Mannitol 62.3 42.8 62.3 42.8 — — — — Ludiflash — — — — 74.4— — — SmartEx — — — — — 74.4 — — QD50 F-Melt — — — — — — 74.4 — ProSolvODT — — — — — — — 74.4 G2 Crospovidone 5.0 5.0 5.0 5.0 — — — — Flavor5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 HIS 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4Buffer 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 MgSt 1.0 1.0 1.0 1.0 1.0 1.0 1.01.0 Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 *CBD sorbedonto carrier in a weight ratio of 1:2

Example 32 Evaluations of Two-Layered Tablets—First Layer of Tablet No.43, 47 and 48

Tablet no. 43, 47 and 48 were each manufactured in three versions, wherethe applied pressure used to press the first layer was 10 kN, 20 kN, and30 kN (single punch device with a punch diameter of 10.0 mm),respectively. Five tablets were made for each of these versions. Foreach version of the tablets 43, 47 and 48, a breaking point test, afragility test and a dissolution time measurement were performed on thefirst layer. For measuring breaking point, a PTB 311 from Pharma Testwas used.

The fragility test involved evaluating the number of crushed layersproduced. When all five were intact, a “pass” grade was assigned,whereas one or more crushed layers is indicated by the number of crushedlayers. Alternatively, friability could be used as a measure of thefragility.

To test dissolution time, the following method was used. 15 mL of 0.02 Mpotassium dihydrogen phosphate-buffer (pH adjusted to 7.4) is added to50 mL of water in a measuring tube with a screw cap. The tablet isinserted in the measuring tube and the screw cap is fastened. Themeasuring tube is fixated horizontally. The measuring tube is vibratedat about 110 RPM such that the tablet can move back and forth in themeasuring tube. The measuring tube is vibrated until the tablet ormodule thereof in question is completely dissolved and the time ofvibration is noted as the dissolution time.

TABLE 28 Fragility test indicates number of tablets crushed duringtesting, or “pass” when no tablets were crushed. Tablet no. 43 Tabletno. 47 Tablet no. 48 Layer 1 Layer 1 Layer 1 Compression (lozenge(lozenge (lozenge Test force [kN] layer) layer) layer) Breaking 10 193N237N 195N point 20 232N 239N 229N 30 205N 249N 220N Fragility 10 PassPass Pass 20 Pass Pass Pass 30 Pass Pass Pass Dissolution 10 9 min, 7sec  6 min, 12 sec 12 min 10 sec time 20 9 min, 41 sec 6 min, 38 sec 13min 32 sec 30 9 min, 50 sec 7 min, 05 sec 16 min 0 sec 

As can be seen from Table 28, the breaking points test reveals thatTablet no. 47 having a first layer based on sorbitol as the sugaralcohol gives a higher breaking point that Tablet no. 43 having a firstlayer based on isomalt as the sugar alcohol. Tablet no.43 showed thatthe version pressed with 30 kN actually had a lower breaking point thanthat pressed with 20 kN, indicating that 30 kN pressing force would betoo high and that the direct compressibility of the sugar alcohol(isomalt) is compromised.

Also, it is observed that all tested layers scored a pass in thefragility test, meaning that none of the five of each version wasevaluated to be fragile or crushed during manufacturing.

Further, dissolution time test showed that sorbitol-based Tablet no.47generally dissolved faster than isomalt-based Tablet no.43. Further, ahigher pressing forces resulted in longer dissolution time.

Finally, Tablet no. 48 is compared with Tablet no.43. Tablet no. 48 issomewhat similar to Tablet no.43, but additionally comprising xanthangum. As seen from Table 28, addition of xanthan gum did not noticeablyaffect breaking point test or fragility test, however, the dissolutiontime was significantly increased from around 9-10 minutes for Tablet no.43 to about 12-16 minutes for Tablet no. 48, demonstrating effect ofxanthan gum to delay dissolution and hence release of its constituents,such as sugar alcohol, flavor, nicotine (if any) etc. While obtainingthe above, no compromising of the masking effect of the first layer wasobserved.

Example 33 Evaluations of Two-Layered Tablets—Second Layer of Tablet No.43-46

Tablet no. 43-46 were each manufactured in three versions, where theapplied pressure used to press the first layer was 10 kN, 20 kN, and 30kN, respectively. Five tablets were made for each of these versions. Foreach version of the tablets 43-46 a breaking point test, a fragilitytest and a dissolution time measurement were performed on the secondlayer.

TABLE 29 Fragility test indicates number of tablets crushed duringtesting, or “pass” when no tablets were crushed. Tablet no. 43 Tabletno. 44 Tablet no. 45 Tablet no. 46 Compr. Layer 2 Layer 2 Layer 2 Layer2 Test force [kN] (FDT layer) (FDT layer) (FDT layer) (FDT layer)Breaking point 10 50N 46N 43N 13N 20 N/A 55N 62N 20N 30 N/A 72N 73N 11NFragility 10 1 tablet 1 tablet 1 tablet 5 tablets 20 N/A Pass Pass 5tablets 30 N/A Pass Pass 5 tablets Dissolution time 10 2 min, 20 sec 50sec 50 sec 35 sec 20 N/A 1 min, 15 sec 50 sec 1 min 40 sec 30 N/A 2 min,08 sec 1 min 17 sec 2 min 50 sec

First, looking at Tablet no.43-45, Table 29 shows that the breakingpoint of the second layers of the produced tablets generally increaseswith increasing compressing force from 10 kN to 30 kN.

Nevertheless, the table also shows that fragility may be a concern. Itis noted that Tablet no.43 performed reasonably well with only 1 tabletbreaking during testing.

Table 29 also shows that a trade-off may exist between applying asufficient compression force to obtain a non-fragile second layer, butthat increasing the compression force also impacts the dissolution time.

Further, it is noted that using disintegrant in the second layer (Tabletno.44-45) resulted in decreased dissolution time over no disintegrant inthe second layer (Tablet no.43), and further that increasing the amountof disintegrant as in Tablet no.45 over Tablet no.44 lead to a furtherdecrease in dissolution time.

Taking also Tablet no.46 into account, it is noted that while veryfragile second modules were produced, a rather short dissolution timewas measured. It is noted that when evaluating the particle sizedistribution of the mannitol used in Tablet no.43-44 and 46, thePearlitol Flash used in Tablet no.44-45, and the erythritol used inTablet no.46, the Pearlitol Flash showed the smallest particles sized,followed by the mannitol, whereas the erythritol applied (a non-DC gradeof erythritol) had significantly larger particles. Using the non-DCgrade erythritol with larger particles resulted in relatively fastdissolution times.

Example 34 Evaluations of Two-Layered Tablets—Whole Tablet of TabletNo.45

Tablet no.45 were made with the compression forces indicated in Table30.

TABLE 30 Whole two-layered tablets. Compression Compression force forceLayer 1 Layer 2 Fragility Dissolution time 10 kN 5 kN Fragile. DecappingN/A layer 1 from layer 2  5 kN 5 kN Not fragile. layer 1: 5 min 20 secNo decapping layer 2: 1 min  8 kN 5 kN Not fragile. layer 1: 6 min Nodecapping layer 2: 1 min  5 kN 2 kN Not fragile. Layer 1: 5 min 30 secNo decapping Layer 2: 45 sec.

Table 30 shows that it is possible to compress layer 1 with acompression force that is higher than the compression force applied tolayer 2, while still obtaining tablets that are not too fragile. It isnoted, however, that decapping of layer 2 from layer 1 may be avoided ifthe compression force applied to layer 1 is not too high.

Furthermore, the measured dissolution times were fully acceptable,particularly since the second layers dissolved within 1 minute, whereasthe first layers all took more than 5 minutes to dissolve.

Example 35 In Vivo Testing of Release

A sample tablet was tested in a test panel of 8 test persons. Testsubjects abstain from eating and drinking at least 30 minutes beforeinitiation of any test. The test person was a healthy person appointedon an objective basis according to specified requirements. After 0, 0.5,1, 2, 3, 5 and 10 minutes, the content of CBD was measured in theremaining tablet residue. The tablet was subject to triple measurementsfor each of the 8 test persons, giving a total of 24 measurements foreach sample. An average of the 24 measurements was calculated and theweight % release was calculated based on the original content of CBD inthe sample. The content of CBD was measured in the remaining tabletresidue, if still present.

The tablet was weighted and placed in the mouth, between the tongue andthe palate. The tablet was sucked and turned every 0.5 minute. Once thedesired test time was achieved (0.5, 1, 2, 3, 5 and 10 min.), the tabletwas taken out and weighed directly into a measuring glass to be used foranalysis of API content. An in vivo dissolution profile was obtained byanalyzing the content of the API in the tablet at different dissolutiontimes.

Example 36 In Vitro Testing of Release

A sample tablet was tested. After 0, 0.5, 1, 2, 3, 5 and 10 minutes, thecontent of CBD was measured in the remaining tablet residue. The tabletwas subject to triple measurements. An average of the measurements wascalculated and the weight % release was calculated based on the originalcontent of CBD in the sample. The content of CBD was measured in theremaining tablet residue, if still present.

The tablet was weighted. Then 25 ml of phosphate buffer was added into a50 ml measuring tube with screw cap. The tablet was added to the tube.The tube was fixed horizontally on a shaking table. After shaking, thetablet was analyzed for content of API. An in vitro profile was obtainedby analyzing the content of the API in the tablet at differentdissolution times.

Example 37 CBD Delivered to the Oral Mucosa

A sample was sucked for 1 minute in a test panel of 8 test persons. Testsubject abstains from eating and drinking at least 30 minutes beforeinitiation of any test. The test person was not allowed to swallowduring the procedure. The tablet was weighted and placed in the mouth,between the tongue and the palate. The tablet was sucked and turnedevery 10 seconds. After one minute, saliva was obtained from the testperson and collected in a vessel for later analysis. In tests for 2minutes release, the same procedure was followed until 2 minutes wherethe last saliva sample was collected and added to the same vessel foraggregated analysis. The test person was a healthy person appointed onan objective basis according to specified requirements. The aggregatedsaliva sample was collected after 2 minutes, and the content of CBD wasmeasured in the saliva. The content of CBD was also measured in theremaining residue. The residue, if still present, was positioned in aflask, weighted and analyzed. The residue, if still present, and salivawere subject to 3 triple measurements for each of the 8 test persons,giving a total of 24 measurement for each sample. An average of the 24measurements was calculated and the weight % release was calculated. Bycomparing the amount of CBD in the residue and the amount of CBD in thesaliva, the amount of CBD delivered to the oral mucosa could beestimated.

Example 38 Sensoric Evaluation Test Set-Up

In addition to release measurements, either in vivo or in vitro,sensoric tests were performed to reveal very important characteristicsand properties of the tablets. These sensoric parameters are importantas indicators of the structure of the tablet composition. The structureis the underlying guidance as to how the tablet resembles the structureof a comparative tablet, which is set as the standard in the testseries, i.e. the tablets are compared to each other in the test seriesof preferably 5 samples. The test set-up was composed of 8 test personsin a test panel. All of the test persons were healthy individualsappointed on an objective basis according to specified requirements. Thesensory analysis was performed according to ISO 4121-2003 in testingconditions following ISO 8589. The result is an average of the resultsof the 8 individuals.

The test persons gave a rating from “+” to “+++++”, where “+” is poorand “+++++” is excellent, i.e. “+++++” means that the tablet wasexcellent compared to the standard, “+++” means that the tablet wascomparable to the standard and “+” means that the tablet was very farfrom comparable to the standard. “0” indicated that it was not tested.

Four different parameters were tested in a test panel:

Friability Flavor Sweetness Off-notes

“Friability”—the impression of the tablet when placed in the mouth andsucking is commenced. For instance, a very hard and viscous structuregave a very low rating and a very brittle structure also gave a very lowrating.

“Flavor”—the overall impression of the tablet during sucking withrespect to flavor. For instance, a very low flavor experience gave avery low rating and a too high flavor experience that was not comparableto the standard also gave a very low rating.

“Sweetness”—the overall impression of the taste of the tablet duringsucking with respect to sweetness. For instance, if the sweetness wasdecreasing rapidly, a very low rating was given and if the sweetness wastoo high giving an uncomfortable feeling, a very low rating was alsogiven.

“Off-notes”—the overall impression of the off-note from the one or morecannabinoids in the composition during sucking. For instance, ifoff-notes (grass, bitter notes, irritation in the throat) wereexperienced in the throat, a low rating was given and if otheruncomfortable sensations was experienced, a low rating was also given.

1. A single-layered compressed cannabinoid tablet, the tablet comprisinga tablet formulation including: a sugar alcohol composition comprisingone or more sugar alcohol particles in an amount of 50 to 90% by weightof the tablet, a cannabinoid composition comprising one or morecannabinoids, and a disintegrant composition comprising one or moredisintegrants in an amount of 0.5 to 25% by weight of the tabletoperable to disintegrate the tablet within a period of 2 minutes or lessthan 2 minutes in contact with oral saliva, wherein at least a part ofthe one or more cannabinoids is reversibly associated with at least apart of the one or more sugar alcohol particles by means of adsorptionto said one or more sugar alcohol particles in a premixture prior tobeing applied in the tablet formulation.
 2. The tablet according toclaim 1, wherein the one or more disintegrants is present in an amountof 2 to 15% by weight of the tablet.
 3. The tablet according to claim 1,wherein the one or more disintegrants is swellable in contact with oralsaliva.
 4. The tablet according to claim 1, wherein the one or moredisintegrants comprises starch.
 5. The tablet according to claim 1,wherein the one or more disintegrants comprises microcrystallinecellulose.
 6. The tablet according to claim 1, wherein the one or moredisintegrants comprises a super disintegrant.
 7. The tablet according toclaim 1, wherein the one or more disintegrants comprises a superdisintegrant selected from the group consisting of sodiumcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof.
 8. The tablet according to claim 1, wherein the one or moredisintegrants comprises cross-linked polyvinylpyrrolidone.
 9. The tabletaccording to claim 1, wherein the one or more sugar alcohol particles isselected from the group consisting of xylitol, lactitol, sorbitol,maltitol, erythritol, isomalt, mannitol, and combinations thereof. 10.The tablet according to claim 1, wherein the premixture is present in aratio of 1:10 to 1:4 by weight of the one or more sugar alcoholparticles.
 11. The tablet according to claim 1, wherein the weight ratioof the one or more cannabinoids relative to the one or more sugaralcohol particles is from 1:30 to 1:1.
 12. The tablet according to claim1, further comprising a binder, such as a dry or wet binder.
 13. Thetablet according to claim 1, wherein the tablet does not include addedliquid solvent for the one or more cannabinoids.
 14. The tabletaccording to claim 1, wherein the one or more cannabinoids is selectedfrom the group consisting of cannabidiol (CBD), cannabidiolic acid(CBDA), cannabidivarin (CBDV), and combinations thereof.
 15. The tabletaccording to claim 1, wherein the one or more cannabinoids is selectedfrom the group consisting of tetrahydrocannabinol (THC),tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), andcombinations thereof.
 16. The tablet according to claim 1, wherein theone or more cannabinoids comprises at least one phytocannabinoid thatforms part of an extract.
 17. The tablet according to claim 1, whereinthe one or more cannabinoids comprises at least one isolatedcannabinoid.
 18. The tablet according to claim 1, wherein the tabletcomprises a self-emulsifying agent.
 19. The tablet according to claim 1,wherein the tablet comprises a lipid carrier for the one or morecannabinoids.
 20. The tablet according to claim 1, wherein the one ormore cannabinoids is not adsorbed to silica.
 21. A compressedcannabinoid tablet, the tablet comprising a tablet formulationincluding: a sugar alcohol composition comprising one or more sugaralcohol particles in an amount of 30 to 90% by weight of the tablet, acannabinoid composition comprising one or more cannabinoids, and adisintegrant composition comprising one or more disintegrants in anamount of 2 to 15% by weight of the tablet operable to disintegrate saidtablet within a period of 2 minutes or less than 2 minutes in contactwith oral saliva, wherein at least a part of the one or morecannabinoids is reversibly associated with at least a part of the one ormore sugar alcohol particles by means of adsorption to said one or moresugar alcohol particles in a premixture prior to being applied in thetablet formulation.
 22. A cannabinoid tablet, the tablet comprising atablet formulation including: a sugar alcohol composition comprising oneor more sugar alcohol particles in an amount of 50 to 90% by weight ofthe tablet, a cannabinoid composition comprising one or morecannabinoids, and a disintegrant composition comprising one or moredisintegrants in an amount of 2 to 15% by weight of the tablet operableto disintegrate said tablet within a period of 2 minutes or less than 2minutes in contact with oral saliva, wherein at least a part of the oneor more cannabinoids is adsorbed to at least a part of the one or moresugar alcohol particles in a premixture prior to being applied in thetablet formulation.
 23. The tablet according to claim 22, wherein thepremixture is present in a ratio of 1:10 to 1:4 by weight of the one ormore sugar alcohol particles.
 24. The tablet according to claim 22,wherein the premixture is present in a ratio of 1:20 to 1:2 by weight ofthe one or more sugar alcohol particles.